Wallace DC. Mitochondria as chi. Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Erratum in: Stem Cell Res Ther. Sánchez-Aragó M, García-Bermúdez J, Martínez-Reyes I, Santacatterina F, Cuezva JM.

Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep. van der Bliek AM, Sedensky MM, Morgan PG. Cell biology of the mitochondrion. Erratum in: Genetics. Hirschey MD, Zhao Y.

Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol Cell Proteomics. Zhang Y, Marsboom G, Toth PT, Rehman J. Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. Plos One. Shum LC, White NS, Mills BN, Bentley KL, Eliseev RA.

Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Sandhir R, Halder A, Sunkaria A. Mitochondria as a centrally positioned hub in the innate immune response. Biochim Biophys Acta Mol Basis Dis. Wang L, Guo X, Guo X, Zhang X, Ren J. Decitabine promotes apoptosis in mesenchymal stromal cells isolated from patients with myelodysplastic syndromes by inducing reactive oxygen species generation.

Eur J Pharmacol. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. Quinn KP, Sridharan GV, Hayden RS, et al. Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation.

Sci Rep. Forni MF, Peloggia J, Trudeau K, Shirihai O, Kowaltowski AJ. Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics.

Stem Cells. Shen Y, Wu L, Qin D, et al. Carbon black suppresses the osteogenesis of mesenchymal stem cells: the role of mitochondria. Part Fibre Toxicol. Jiang D, Gao F, Zhang Y, et al. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage.

Cell Death Dis. Jiang B, Yan L, Wang X, et al. Concise review: mesenchymal stem cells derived from human pluripotent cells, an unlimited and quality-controllable source for therapeutic applications.

Article PubMed Google Scholar. Chang CH, Curtis JD, Maggi LB Jr, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Jiang D, Chen FX, Zhou H, et al. Bioenergetic crosstalk between mesenchymal stem cells and various ocular cells through the intercellular trafficking of mitochondria.

Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS.

Burt R, Dey A, Aref S, et al. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Luz-Crawford P, Hernandez J, Djouad F, et al. Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Islam MN, Das SR, Emin MT, et al.

Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. Court AC, Le-Gatt A, Luz-Crawford P, et al.

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. Morrison TJ, Jackson MV, Cunningham EK, et al.

Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer.

Am J Respir Crit Care Med. Xu X, Duan S, Yi F, et al. Mitochondrial regulation in pluripotent stem cells. Cell Metab. Caicedo A, Aponte PM, Cabrera F, Hidalgo C, Khoury M. Artificial mitochondria transfer: current challenges, advances, and future applications. Stem Cells Int. Wood Dos Santos T, Cristina Pereira Q, Teixeira L, et al.

Effects of polyphenols on thermogenesis and mitochondrial biogenesis. Int J Mol Sci. Article PubMed Central CAS Google Scholar. Li PA, Hou X, Hao S.

Mitochondrial biogenesis in neurodegeneration. J Neurosci Res. Hsu YC, Wu YT, Yu TH, Wei YH. Mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol. Wanet A, Remacle N, Najar M, et al. Mitochondrial remodeling in hepatic differentiation and dedifferentiation.

Int J Biochem Cell Biol. Otera H, Mihara K. Molecular mechanisms and physiologic functions of mitochondrial dynamics. J Biochem.

Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. Otera H, Ishihara N, Mihara K. New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta. Han YS, Kim SM, Lee JH, et al. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC-dependent enhancement of the mitochondrial function.

J Pineal Res. Article PubMed CAS Google Scholar. Pasztorek M, Rossmanith E, Mayr C, et al. Influence of platelet lysate on 2D and 3D amniotic mesenchymal stem cell cultures.

Front Bioeng Biotechnol. Park S, Choi SG, Yoo SM, et al. Pyruvate stimulates mitophagy via PINK1 stabilization. Cell Signal. Lazarou M, Sliter DA, Kane LA, et al.

The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.

J Cell Biol. Nuschke A, Rodrigues M, Stolz DB, et al. Song BQ, Chi Y, Li X, et al. Cell Physiol Biochem. Zhang H, Menzies KJ, Auwerx J. The role of mitochondria in stem cell fate and aging.

Tsujimoto T, Mori T, Houri K, et al. miR inhibits mitophagy through suppression of BAG5, a partner protein of PINK1. Biochem Biophys Res Commun. Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Pattappa G, Thorpe SD, Jegard NC, et al.

Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells.

Tissue Eng Part C Methods. Baker N, Boyette LB, Tuan RS. Characterization of bone marrow-derived mesenchymal stem cells in aging. Tahara EB, Navarete FD, Kowaltowski AJ.

Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med.

Tang Y, Luo B, Deng Z, et al. Mitochondrial aerobic respiration is activated during hair follicle stem cell differentiation, and its dysfunction retards hair regeneration. Shares BH, Busch M, White N, Shum L, Eliseev RA. Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation.

J Biol Chem. Rahman MS, Kim YS. Jin Y, Shen Y, Su X, et al. The small GTPases Rab27b regulates mitochondrial fatty acid oxidative metabolism of cardiac mesenchymal stem cells. Front Cell Dev Biol. Matilainen O, Quirós PM, Auwerx J. Mitochondria and epigenetics-crosstalk in homeostasis and stress.

Trends Cell Biol. Menzies KJ, Zhang H, Katsyuba E, Auwerx J. Protein acetylation in metabolism - metabolites and cofactors. Nat Rev Endocrinol.

Folmes CD, Nelson TJ, Dzeja PP, Terzic A. Energy metabolism plasticity enables stemness programs. Ann N Y Acad Sci. Everts B, Amiel E, van der Windt GJ, et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Seok J, Jung HS, Park S, et al.

Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells. Lee JH, Yoon YM, Song KH, Noh H, Lee SH.

Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway.

Aging Cell. Hu Y, Huang L, Shen M, et al. Pioglitazone protects compression-mediated apoptosis in nucleus pulposus mesenchymal stem cells by suppressing oxidative stress.

Oxid Med Cell Longev. Feng J, Li X, Zhu S, et al. Lasers Med Sci. Varum S, Rodrigues AS, Moura MB, et al. Energy metabolism in human pluripotent stem cells and their differentiated counterparts. Wang W, Zhang Y, Lu W, Liu K. Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine.

Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J. Atashi F, Modarressi A, Pepper MS. The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Tangtrongsup S, Kisiday JD.

Modulating the oxidative environment during mesenchymal stem cells chondrogenesis with serum increases collagen accumulation in agarose culture. J Orthop Res. CAS PubMed Google Scholar. Babizhayev MA, Yegorov YE. Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies.

J Biomed Mater Res A. Chen PM, Lin CH, Li NT, et al. Jin HJ, Lee HJ, Heo J, et al. Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells.

Antioxid Redox Signal. Gu Y, Li T, Ding Y, et al. Changes in mesenchymal stem cells following long-term culture in vitro. Mol Med Rep. Zheng Q, Zhao Y, Guo J, et al. Chen Y, Xiong S, Zhao F, et al.

Effect of magnesium on reducing the UV-induced oxidative damage in marrow mesenchymal stem cells. Oh JY, Choi GE, Lee HJ, et al. Li CJ, Chen PK, Sun LY, Pang CY.

Enhancement of Mitochondrial Transfer by Antioxidants in Human Mesenchymal Stem Cells. Stannard GA, Heather LC. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease.

Mahato B, Home P, Rajendran G, et al. Li B, Li C, Zhu M, et al. Hypoxia-induced mesenchymal stromal cells exhibit an enhanced therapeutic effect on radiation-induced lung injury in mice due to an increased proliferation potential and enhanced antioxidant ability.

Contreras-Lopez R, Elizondo-Vega R, Paredes MJ, et al. FASEB J. Takubo K, Nagamatsu G, Kobayashi CI, et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.

Hsu SH, Chen CT, Wei YH. Inhibitory effects of hypoxia on metabolic switch and osteogenic differentiation of human mesenchymal stem cells. Fujisawa K, Hara K, Takami T, et al. Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells. Alptekin A, Ye B, Ding HF.

Transcriptional regulation of stem cell and cancer stem cell metabolism. Curr Stem Cell Rep. Huang PI, Chen YC, Chen LH, et al. PGC-1α mediates differentiation of mesenchymal stem cells to brown adipose cells. J Atheroscler Thromb.

St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Katsyuba E, Auwerx J. EMBO J. Wu Y, Williams EG, Dubuis S, et al. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.

Zhang H, Ryu D, Wu Y, et al. Lin CH, Li NT, Cheng HS, Yen ML. Chen H, Liu X, Chen H, et al. Role of SIRT1 and AMPK in mesenchymal stem cells differentiation. Ageing Res Rev. Denu RA, Hematti P. Effects of oxidative stress on mesenchymal stem cell biology.

Gao J, Feng Z, Wang X, et al. Cell Death Differ. Jeong SG, Cho GW. Trichostatin A modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow-mesenchymal stem cells.

Cell Biochem Funct. Wu J, Niu J, Li X, et al. TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production. BMC Dev Biol.

Konari N, Nagaishi K, Kikuchi S, Fujimiya M. Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo.

Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Zhao X, Pathak JL, Huang W, et al. Metformin enhances osteogenic differentiation of stem cells from human exfoliated deciduous teeth through AMPK pathway.

J Tissue Eng Regen Med. Kim EK, Lim S, Park JM, et al. Human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by AMP-activated protein kinase. Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase AMPK and cancer: many faces of a metabolic regulator.

Cancer Lett. Pantovic A, Krstic A, Janjetovic K, et al. Tormos KV, Anso E, Hamanaka RB, et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Lu Y, Fujioka H, Joshi D, et al. Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge.

Cedikova M, Kripnerová M, Dvorakova J, et al. Mitochondria in white, brown, and beige adipocytes. Merlin J, Sato M, Chia LY, et al. Rosiglitazone and a β3-adrenoceptor agonist are both required for functional browning of white adipocytes in culture.

Front Endocrinol Lausanne. Michurina S, Stafeev I, Podkuychenko N, et al. Decreased UCP-1 expression in beige adipocytes from adipose-derived stem cells of type 2 diabetes patients associates with mitochondrial ROS accumulation during obesity.

Diabetes Res Clin Pract. Di Somma M, Schaafsma W, Grillo E, et al. Natural histogel-based bio-scaffolds for sustaining angiogenesis in beige adipose tissue.

Andrews ZB, Diano S, Horvath TL. Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci.

Download references. This work was supported by the National Sciences Foundation of China to Z. Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, , China.

Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China. Department of Pediatric dentistry, Capital Medical University School of Stomatology, Beijing, , China. You can also search for this author in PubMed Google Scholar. WY was responsible for conception and design, manuscript writing, creation of figure and table, and final approval of the manuscript.

SD was responsible for search of literature, manuscript writing, financial support, and final approval of the manuscript. FZP was responsible for conception and design, manuscript writing and revising, financial support, and final approval of the manuscript.

All authors have read and approved the final version of the manuscript. So, in reality, these organelles are linked together in ever-changing networks. Also, in sperm cells, the mitochondria are spiraled in the midpiece and provide energy for tail motion. Although most of our DNA is kept in the nucleus of each cell, mitochondria have their own set of DNA.

Interestingly, mitochondrial DNA mtDNA is more similar to bacterial DNA. The mtDNA holds the instructions for a number of proteins and other cellular support equipment across 37 genes. The human genome stored in the nuclei of our cells contains around 3.

However, the child always receives their mtDNA from their mother. Because of this, mtDNA has proven very useful for tracing genetic lines. For instance, mtDNA analyses have concluded that humans may have originated in Africa relatively recently, around , years ago, descended from a common ancestor, known as mitochondrial Eve.

Although the best-known role of mitochondria is energy production, they carry out other important tasks as well. In fact, only about 3 percent of the genes needed to make a mitochondrion go into its energy production equipment. The vast majority are involved in other jobs that are specific to the cell type where they are found.

ATP, a complex organic chemical found in all forms of life, is often referred to as the molecular unit of currency because it powers metabolic processes. Most ATP is produced in mitochondria through a series of reactions, known as the citric acid cycle or the Krebs cycle.

Mitochondria convert chemical energy from the food we eat into an energy form that the cell can use. This process is called oxidative phosphorylation. The Krebs cycle produces a chemical called NADH. NADH is used by enzymes embedded in the cristae to produce ATP.

In molecules of ATP, energy is stored in the form of chemical bonds. When these chemical bonds are broken, the energy can be used. Cell death, also called apoptosis, is an essential part of life.

As cells become old or broken, they are cleared away and destroyed. Mitochondria help decide which cells are destroyed. Mitochondria release cytochrome C, which activates caspase, one of the chief enzymes involved in destroying cells during apoptosis. Because certain diseases, such as cancer , involve a breakdown in normal apoptosis, mitochondria are thought to play a role in the disease.

Calcium is vital for a number of cellular processes. For instance, releasing calcium back into a cell can initiate the release of a neurotransmitter from a nerve cell or hormones from endocrine cells.

Calcium is also necessary for muscle function, fertilization, and blood clotting, among other things. Because calcium is so critical, the cell regulates it tightly.

Mitochondria play a part in this by quickly absorbing calcium ions and holding them until they are needed. Other roles for calcium in the cell include regulating cellular metabolism, steroid synthesis , and hormone signaling.

When we are cold, we shiver to keep warm. But the body can also generate heat in other ways, one of which is by using a tissue called brown fat. During a process called proton leak , mitochondria can generate heat. This is known as non-shivering thermogenesis.

Brown fat is found at its highest levels in babies, when we are more susceptible to cold, and slowly levels reduce as we age. However, the majority of mitochondrial diseases are due to mutations in nuclear DNA that affect products that end up in the mitochondria.

These mutations can either be inherited or spontaneous. When mitochondria stop functioning, the cell they are in is starved of energy. So, depending on the type of cell, symptoms can vary widely. As a general rule, cells that need the largest amounts of energy, such as heart muscle cells and nerves, are affected the most by faulty mitochondria.

Diseases that generate different symptoms but are due to the same mutation are referred to as genocopies. Autophagy 12 4 , — Chen, Y. Mitochondrial Fusion Is Essential for Organelle Function and Cardiac Homeostasis. Chesney, J. An Inducible Gene Product for 6-PhosphofructoKinase with an Au-Rich Instability Element: Role in Tumor Cell Glycolysis and the Warburg Effect.

Cho, Y. Dynamic Changes in Mitochondrial Biogenesis and Antioxidant Enzymes during the Spontaneous Differentiation of Human Embryonic Stem Cells.

Biophysical Res. Christofk, H. The M2 Splice Isoform of Pyruvate Kinase Is Important for Cancer Metabolism and Tumour Growth. Nature , — Pyruvate Kinase M2 Is a Phosphotyrosine-Binding Protein. Chung, S.

Mitochondrial Oxidative Metabolism Is Required for the Cardiac Differentiation of Stem Cells. Cieślar-Pobuda, A. The Expression Pattern of PFKFB3 Enzyme Distinguishes between Induced-Pluripotent Stem Cells and Cancer Stem Cells.

Oncotarget 6 30 , — Civiletto, G. OPA1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models. Clem, B. Small-Molecule Inhibition of 6-PhosphofructoKinase Activity Suppresses Glycolytic Flux and Tumor Growth.

Cancer Therap. Cogliati, S. Mitochondrial Cristae: Where Beauty Meets Functionality. Trends Biochem. Cowie, M. The Epidemiology of Heart Failure. Heart J. Csiszar, A. Resveratrol Induces Mitochondrial Biogenesis in Endothelial Cells.

Physiology-Heart Circulatory Physiology 1 , H13—H Dai, D. Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes. Stem Cells Int. Dean, M. Tumour Stem Cells and Drug Resistance.

Cancer 5 4 , — DeBerardinis, R. Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer. Oncogene 29 3 , — The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Beyond Aerobic Glycolysis: Transformed Cells Can Engage in Glutamine Metabolism that Exceeds the Requirement for Protein and Nucleotide Synthesis.

Deng, P. Desai, S. Regulation of Mitophagy by the Ubiquitin Pathway in Neurodegenerative Diseases. Maywood 6 , — De Bock, K. Role of PFKFB3-Driven Glycolysis in Vessel Sprouting. Ding, L. Involvement of P38mapk and Reactive Oxygen Species in Icariin-Induced Cardiomyocyte Differentiation of Murine Embryonic Stem Cells In Vitro.

Stem Cells Dev. Dobrina, A. Metabolic Properties of Freshly Isolated Bovine Endothelial Cells. Biochimica Biophysica Acta BBA - Mol. Drawnel, F. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy Using Human Induced Pluripotent Stem Cells.

Dyck, J. Characterization of Cardiac Malonyl-COA Decarboxylase and its Putative Role in Regulating Fatty Acid Oxidation. Physiology-Heart Circulatory Physiology 6 , H—H Characterization of Rat Liver Malonyl-COA Decarboxylase and the Study of its Role in Regulating Fatty Acid Metabolism.

Dyer, A. Antagonism of Glycolysis and Reductive Carboxylation of Glutamine Potentiates Activity of Oncolytic Adenoviruses in Cancer Cells. Cancer Res. Eagle, H. Nutrition Needs of Mammalian Cells in Tissue Culture. Science , — Egbuche, O. Contemporary Pharmacologic Management of Heart Failure with Reduced Ejection Fraction: A Review.

Ccr 16 1 , 55— Elgass, K. Recent Advances into the Understanding of Mitochondrial Fission. Fendt, S. Reductive Glutamine Metabolism Is a Function of the α-ketoglutarate to Citrate Ratio in Cells. Feng, X. The Involvement of Mitochondrial Fission in Maintenance of the Stemness of Bone Marrow Mesenchymal Stem Cells.

Maywood 1 , 64— Ferrere, G. Ketogenic Diet and Ketone Bodies Enhance the Anticancer Effects of PD-1 Blockade. JCI Insight 6 2 , e Fillmore, N. Effect of Fatty Acids on Human Bone Marrow Mesenchymal Stem Cell Energy Metabolism and Survival.

PLOS ONE 10 3 , e Finck, B. The PPAR Regulatory System in Cardiac Physiology and Disease. Folmes, C. Metabolic Plasticity in Stem Cell Homeostasis and Differentiation. Stem Cell. Energy Metabolism Plasticity Enables STEMNESS Programs.

Somatic Oxidative Bioenergetics Transitions into Pluripotency-dependent Glycolysis to Facilitate Nuclear Reprogramming. Forni, M. Murine Mesenchymal Stem Cell Commitment to Differentiation Is Regulated by Mitochondrial Dynamics. Stem Cells 34, — Fröhlich, C.

Structural Insights into Oligomerization and Mitochondrial Remodelling of Dynamin 1-like Protein. Embo J. Fu, W. Mitochondrial Dynamics: Biogenesis, Fission, Fusion, and Mitophagy in the Regulation of Stem Cell Behaviors.

Fujiwara, M. The Mitophagy Receptor Bcllike Protein 13 Stimulates Adipogenesis by Regulating Mitochondrial Oxidative Phosphorylation and Apoptosis in Mice. Fukushima, A. Acetylation Contributes to Hypertrophy-Caused Maturational Delay of Cardiac Energy Metabolism.

JCI Insight 3 10 , e Garbern, J. Mitochondria and Metabolic Transitions in Cardiomyocytes: Lessons from Development for Stem Cell-Derived Cardiomyocytes. Garnett, M. Pyruvate Kinase Isozyme Changes in Parenchymal Cells of Regenerating Rat Liver.

Gegg, M. Gilde, A. Circulation Res. Gilkerson, R. The Cristal Membrane of Mitochondria Is the Principal Site of Oxidative Phosphorylation.

FEBS Lett. Girard, J. Adaptations of Glucose and Fatty Acid Metabolism during Perinatal Period and Suckling-Weaning Transition. Gleyzer, N. Control of Mitochondrial Transcription Specificity Factors TFB1M and TFB2M by Nuclear Respiratory Factors NRF-1 and NRF-2 and PGC-1 Family Coactivators.

Gong, G. Mitochondrial Flash as a Novel Biomarker of Mitochondrial Respiration in the Heart. Physiology-Heart Circulatory Physiology , H—H Parkin-Mediated Mitophagy Directs Perinatal Cardiac Metabolic Maturation in Mice.

Science , Gulick, T. The Peroxisome Proliferator-Activated Receptor Regulates Mitochondrial Fatty Acid Oxidative Enzyme Gene Expression. Hansson, J. Highly Coordinated Proteome Dynamics during Reprogramming of Somatic Cells to Pluripotency.

Hardie, D. Regulation of Fatty Acid and Cholesterol Metabolism by the AMP-Activated Protein Kinase. Biochimica Biophysica Acta BBA - Lipids Lipid Metabolism 3 , — Regulation of Fatty Acid Synthesis via Phosphorylation of Acetyl-COA Carboxylase.

Lipid Res. Hasan-Olive, M. A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis. Hauck, L. Death Differ. Heallen, T. Stimulating Cardiogenesis as a Treatment for Heart Failure.

Targeting Mitochondrial Fusion and Fission Proteins for Cardioprotection. Ho, T. Autophagy Maintains the Metabolism and Function of Young and Old Stem Cells. Hom, J. The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation. Hoppins, S.

The Machines that Divide and Fuse Mitochondria. Hoque, A. Mitochondrial Fission Protein DRP1 Inhibition Promotes Cardiac Mesodermal Differentiation of Human Pluripotent Stem Cells.

Death Discov. Horikoshi, Y. Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-like Energy Metabolism Phenotypes. Cells 8 9 , Hu, C. Drp1-Dependent Mitochondrial Fission Plays Critical Roles in Physiological and Pathological Progresses in Mammals.

Ijms 18 1 , Hue, L. Fructose 2,6-Bisphosphate and the Control of Glycolysis by Growth Factors, Tumor Promoters and Oncogenes.

Enzyme Regul. Huo, L. Mitochondrial DNA Instability and Peri-Implantation Lethality Associated with Targeted Disruption of Nuclear Respiratory Factor 1 in Mice.

Huss, J. Nuclear Receptor Signaling and Cardiac Energetics. Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle. Ikeda, Y. Allosteric Regulation of Pyruvate Kinase M2 Isozyme Involves a Cysteine Residue in the Intersubunit Contact.

Ishihara, T. Dynamics of Mitochondrial DNA Nucleoids Regulated by Mitochondrial Fission Is Essential for Maintenance of Homogeneously Active Mitochondria during Neonatal Heart Development.

Itoi, T. The Contribution of Glycolysis, Glucose Oxidation, Lactate Oxidation, and Fatty Acid Oxidation to ATP Production in Isolated Biventricular Working Hearts from 2-Week-Old Rabbits.

Jäger, S. AMP-activated Protein Kinase AMPK Action in Skeletal Muscle via Direct Phosphorylation of PGC-1α. Jain, M. Increased Myocardial Dysfunction after Ischemia-Reperfusion in Mice Lacking GlucosePhosphate Dehydrogenase. Circulation 7 , — Jensen, J. The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise.

Jurkin, J. Distinct and Redundant Functions of Histone Deacetylases HDAC1 and HDAC2 in Proliferation and Tumorigenesis. Cycle 10 3 , — Kageyama, Y. Kane, A. Kane, L. PINK1 Phosphorylates Ubiquitin to Activate Parkin e3 Ubiquitin Ligase Activity.

Karbassi, E. Cardiomyocyte Maturation: Advances in Knowledge and Implications for Regenerative Medicine. Kasahara, A. Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch Signaling. Khacho, M. Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.

Kletzien, R. FASEB J. Knoepfler, P. Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine. Stem Cells 27 5 , — Kolwicz, S. Cardiac Metabolism and its Interactions with Contraction, Growth, and Survival of Cardiomyocytes.

Kondoh, H. A High Glycolytic Flux Supports the Proliferative Potential of Murine Embryonic Stem Cells. Antioxidants Redox Signal. Kovačević, Z. The Pathway of Glutamine and Glutamate Oxidation in Isolated Mitochondria from Mammalian Cells. Koyano, F.

Ubiquitin Is Phosphorylated by PINK1 to Activate Parkin. Kraus, F. The Constriction and Scission Machineries Involved in Mitochondrial Fission. Kung, C. Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy. Kuroda, Y. Parkin Enhances Mitochondrial Biogenesis in Proliferating Cells.

Lai, L. Transcriptional Coactivators PGC-1α and PGC-Lβ Control Overlapping Programs Required for Perinatal Maturation of the Heart. Lam, V. Activating PPARα Prevents Post-Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts.

Lampert, M. Autophagy 15 7 , — Lees, J. Mitochondrial Fusion by M1 Promotes Embryoid Body Cardiac Differentiation of Human Pluripotent Stem Cells. Lehman, J. Peroxisome Proliferator-Activated Receptor γ Coactivator-1 Promotes Cardiac Mitochondrial Biogenesis. Lehninger, A.

Principles of Biochemistry. New York: Worth Publisher. Lelliott, C. Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance.

PLoS Biol. Lemasters, J. Selective Mitochondrial Autophagy, or Mitophagy, as a Targeted Defense against Oxidative Stress, Mitochondrial Dysfunction, and Aging. Rejuvenation Res. Leone, T. PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis.

A Critical Role for the Peroxisome Proliferator-Activated Receptor α PPARα in the Cellular Fasting Response: The PPARα-Null Mouse as a Model of Fatty Acid Oxidation Disorders.

Li, B. G6PD, Bond by Mir, Regulates Mitochondrial Dysfunction and Oxidative Stress in Phenylephrine-Induced Hypertrophic Cardiomyocytes. Life Sci. Li, D. A New G6PD Knockdown Tumor-Cell Line with Reduced Proliferation and Increased Susceptibility to Oxidative Stress.

Cancer Biotherapy Radiopharm. Li, T. PKM2 Coordinates Glycolysis with Mitochondrial Fusion and Oxidative Phosphorylation. Protein Cell. Li, X. Alternate-Day High-Fat Diet Induces an Increase in Mitochondrial Enzyme Activities and Protein Content in Rat Skeletal Muscle.

Nutrients 8 4 , Liesa, M. Mitochondrial Dynamics in Mammalian Health and Disease. Liu, L. Mitochondrial Outer-Membrane Protein FUNDC1 Mediates Hypoxia-Induced Mitophagy in Mammalian Cells.

Liu, Y. PGC-1α Activator ZLN Promotes Maturation of Cardiomyocytes Derived from Human Embryonic Stem Cells. Aging 12 8 , — Longo, L. Maternally Transmitted Severe Glucose 6-Phosphate Dehydrogenase Deficiency Is an Embryonic Lethal. EMBO J. Lopaschuk, G.

Regulation of Fatty Acid Oxidation in the Mammalian Heart in Health and Disease. Developmental Changes in Energy Substrate Use by the Heart. The Merck Frosst Award.

Acetyl-COA Carboxylase: An Important Regulator of Fatty Acid Oxidation in the Heart. Cardiac Energy Metabolism in Heart Failure. Glycolysis Is Predominant Source of Myocardial ATP Production Immediately after Birth.

Myocardial Fatty Acid Metabolism in Health and Disease. Acetyl-COA Carboxylase Involvement in the Rapid Maturation of Fatty Acid Oxidation in the Newborn Rabbit Heart. Lunt, S. Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation. MacVicar, T.

Impaired OMA1 Dependent OPA1 Cleavage and Reduced DRP1 Fission Activity Combine to Prevent Mitophagy in OXPHOS Dependent Cells. Magadum, A. PKM2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.

Circulation 15 , — Makinde, A. Maturation of Fatty Acid and Carbohydrate Metabolism in the Newborn Heart. Mandal, S. Mitochondrial Function Controls Proliferation and Early Differentiation Potential of Embryonic Stem Cells.

Stem Cells 29 3 , — Marsboom, G. Glutamine Metabolism Regulates the Pluripotency Transcription Factor OCT4. Martin, O. A Role for Peroxisome Proliferator-Activated Receptor γ Coactivator-1 in the Control of Mitochondrial Dynamics during Postnatal Cardiac Growth.

Mascaró, C. Control of Human Muscle-type Carnitine Palmitoyltransferase I Gene Transcription by Peroxisome Proliferator-Activated Receptor. Mayor, F. Hormonal and Metabolic Changes in the Perinatal Period.

Neonatology 48 4 , — McMillin, J. Kinetic Properties of Carnitine Palmitoyltransferase I in Cultured Neonatal Rat Cardiac Myocytes. Archives Biochem. Biophysics 2 , — McMurray, J. The Burden of Heart Failure. Medina, J. The Role of Lactate as an Energy Substrate for the Brain during the Early Neonatal Period.

Miao, S. Retinoic Acid Promotes Metabolic Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes. Theranostics 10 21 , — Mierziak, J. Biomolecules 11 3 , Mishra, P. Metabolic Regulation of Mitochondrial Dynamics.

Momtahan, N. The Role of Reactive Oxygen Species in In Vitro Cardiac Maturation. Trends Mol. Mummery, C. Differentiation of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells to Cardiomyocytes.

Murray, T. NADPH Oxidase 4 Regulates Cardiomyocyte Differentiation via Redox Activation of C-Jun Protein and the Cis-Regulation of GATA-4 Gene Transcription.

Nakano, H. Glucose Inhibits Cardiac Muscle Maturation through Nucleotide Biosynthesis. eLife 6, e Newman, J. Ketone Bodies as Signaling Metabolites. Trends Endocrinol.

Metabolism 25 1 , 42— Nikoletopoulou, V. Crosstalk between Apoptosis, Necrosis and Autophagy. Nissler, K. Fructose 2,6-Bisphosphate Metabolism in Ehrlich Ascites Tumour Cells.

Nose, N. Metabolic Substrate Shift in Human Induced Pluripotent Stem Cells during Cardiac Differentiation: Functional Assessment Using In Vitro Radionuclide Uptake Assay. Novellasdemunt, L. Ong, S. Circulation 18 , — Orogo, A.

Cell Death in the Myocardium: My Heart Won't Go on. IUBMB Life 65 8 , — Ortiz-Sandoval, C. Interaction with the Effector Dynamin-Related Protein 1 Drp1 Is an Ancient Function of Rab32 Subfamily Proteins. Pagliarini, D. A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology.

Palikaras, K. Mitochondrial Homeostasis: The Interplay between Mitophagy and Mitochondrial Biogenesis. Panadero, M. Peroxisome Proliferator-Activated Receptor-α Expressionin Rat Liver during Postnatal Development. Biochimie 82 8 , — Pandolfi, P.

Targeted Disruption of the Housekeeping Gene Encoding Glucose 6-Phosphate Dehydrogenase G6PD : G6PD Is Dispensable for Pentose Synthesis but Essential for Defense against Oxidative Stress. Papanicolaou, K.

An important step in glucose oxidation is the initial mitochondrial uptake of pyruvate derived from glycolysis by the mitochondrial pyruvate carrier MPC complex, which transfers pyruvate into the mitochondria to undergo further metabolism.

MPC is found in low levels in intestinal stem cells, and in high amounts when these cells are differentiated Schell et al. When glucose oxidation is blocked through the of deletion of MPC, there is an increase in stem cell number and proliferation Schell et al. Similarly, if PDH, a key enzyme that converts pyruvate to acetyl CoA, is disrupted with RNAi, there is an increase in ISC proliferation Schell et al.

This indicates the important role that glucose oxidation plays in the regulation of stem cell fate, as inhibiting glucose oxidation through the inhibition of MPC or PDH leads to an increased stem-like state with increased proliferation. Once stem cells differentiate, they become metabolically more active, and depend more on oxidative phosphorylation for energy production compared to glycolysis Zhang et al.

As previously mentioned, these metabolic shifts are tightly linked to mitochondrial dynamics. If Drp1 is blocked in hiPSCs differentiating into cardiomyocytes, there is an inhibition of mitochondrial fission and a shift from glycolysis toward oxidative phosphorylation Hoque et al.

The Warburg effect is a metabolic state in which there are high rates of glycolysis uncoupled from glucose oxidation under aerobic conditions, leading to increased production of lactate. The Warburg effect is typically seen in cancerous cells and actively proliferating cells Abdel-Haleem et al.

In cancer cells, a high Warburg effect promotes their growth, survival, and proliferation. Given that stem cells have a high rate of glycolysis, even in the presence of oxygen, they also exhibit the Warburg effect Chung et al. This is thought to be due to a low copy number of mtDNA within stem cells, leading to more immature mitochondria Chen C.

As previously mentioned, although the Warburg effect is inefficient in its ability to produce ATP, the carbons from glucose can be used for anabolic processes needed to support cell proliferation DeBerardinis et al. Particularly, there is a greater synthesis of reducing equivalent in the PPP, such as reduced NADPH, which is highly consumed during the synthesis of amino acids and nucleotides needed to replicate cellular content during division Lehninger et al.

When stem cells differentiate and mature, there is a reversal of the Warburg effect, as evidenced by a decrease in glycolysis and an increase in oxidative phosphorylation, as discussed above, to better support the needs of the differentiated cells Shyh-Chang et al. This reduction in glycolysis is indicative of a reduced Warburg effect.

Interestingly, glucose oxidation still remains low during this time, most likely due to an increase in PDK expression, which phosphorylates and inhibits PDH Lopaschuk et al.

As discussed previously, glucose oxidation does not fully mature in the heart until the infant is weaned Girard et al. Rather, the heart switches from primarily glycolytic metabolism to fatty acid oxidation immediately post birth Lopashuk et al.

This switch is also seen in hiPSC-CMs Nose et al. Exposure to high levels of glucose leads to an impaired differentiation into cardiomyocytes, seen in both human and mouse ESCs Yang et al.

Conversely, suppressing glucose levels supplements the differentiation and maturation of hiPSC-CMs Nakano et al. Together, this indicates the reliance that proliferating stem cells or immature cardiomyocytes have on the Warburg effect, and that this is reversed during differentiation and maturation.

Pyruvate kinase dephosphorylates phosphoenolpyruvate during glycolysis, producing ATP and pyruvate. As discussed previously, anabolic metabolism is integral to proliferative capacity.

PKM2 is mainly expressed in proliferating cells; however, it has lower enzymatic activity compared to PKM1 which is mainly expressed in adult cells Garnett et al.

In proliferating cells, PKM2 exists in a dimer conformation, which has a lower enzymatic activity and promotes an increase in anabolic metabolism, through the PPP, which subsequently allows for the synthesis of biomolecules necessary for proliferation Ikeda and Noguchi, PKM2 can shift into an active tetrameric conformation by upstream F-1,6-BP Ashizawa et al.

In contrast, phosphotyrosine-marked proteins revert PKM2 to a lower activity conformation, through a dissociation of F-1,6-BP Christofk et al. As such, small molecule activators of PKM2 have been studied as a way to induce the active tetrameric conformation of PKM2, which resemble the effects of PKM1 substitution studies, leading to decreased tumorgenicity Christofk et al.

Overall, studies in which PKM2 is activated to its tetrameric conformation were shown to lead to a decrease in the cells ability to proliferate Anastasiou et al. PKM2 also seems to play a role in the fate of pyruvate, as it can be reduced to lactate or oxidized to acetyl-CoA for further pyruvate oxidation.

Increased PKM2 activity leads to an increase in the amount of pyruvate being used for mitochondrial oxidative metabolism, and a reduced production of lactate Christofk et al. This may be due to an increase in PKM2 binding to Mfn2, which promotes mitochondrial fusion, through mTOR, which subsequently leads to an increase in oxidative phosphorylation and a decrease in glycolysis Li et al.

While the knockdown of PKM2 decreases glycolytic activity in cancer cells, increasing PKM2 is able to restore both glycolysis and oxidative phosphorylation Li et al. Notably, in glycolysis defective mutated PKM2, restoration of PKM2 in PKM2 deficient cells still leads to a partial increase in oxidative phosphorylation, indicating that PKM2s regulation of oxidative metabolism is partially independent of its effects on glycolysis Li et al.

During cardiomyocyte development, PKM2 appears to have a significant role, as it is highly expressed during development and immediately after birth, although it is replaced by PKM1 in the adult cardiomyocyte Magadum et al.

In PKM2 deletion studies, myocardial size and cardiomyocyte quantity are reduced Magadum et al. The issue of whether enhanced or lowered PKM2 is important in inducing proliferation post myocardial infarction MI has produced controversial results.

Magadum et al. Notably, neither of these studies demonstrates whether their results were aligned with the dimer or tetramer conformation of PKM2. As such, more research regarding the role of PKM2 in cardiomyocyte proliferation and differentiation is necessary. The role of PFKF3B in cell fate has been mainly studied in the context of cancer and angiogenesis the process of forming new blood vessels.

PFKFB3 is responsible for an increased synthesis of fructose-2,6-bisphosphatase F-2,6-BP , which allosterically regulates phosphofructkinase-1 PFK-1 Pilkis et al. PFK-1 catalyzes a key rate-limiting step of glycolysis, the conversion of fructosephosphate to F-1,6-BP Ros and Shulze, PFKFB3 is associated with an increase in glycolysis within cancer cells, as seen by increases in PFKFB3 expression and phosphorylation Novellasdemunt et al.

It has been shown that F-2,6-BP is upregulated in cancerous cells, associated with stimulation of glycolysis, and its depletions can suppress cell survival and proliferation Hue and Rousseau.

As such, the inhibition of PFKFB3, and the subsequent decrease in F-2,6-BP, has been examined to determine its effects on tumor growth and cell death Seo et al. Cancer stem cells CSCs are a type of cells within tumors that are capable of self-renewal and differentiation Wicha et al. These CSCs are typically resistant to cancer treatments Dean et al.

High levels of PFKFB3 are characteristic of CSCs compared to iPSCs and other cancer cells Cieślar-Pobuda et al. This is important because in the process of transplanting iPSCs, there is the possibility of cancerous tumor formation due to the presence of undifferentiated IPSCs Knoepfler, As such, being able to differentiate between CSCs and normal stem cells is critical to the use of iPSCs in regenerative medicine.

PFKFB3 has also been studied in endothelial cells ECs during angiogenesis. ECs consume high levels of glucose and exhibit the Warburg effect, as they are highly glycolytic, even in the presence of oxygen Dobrina and Rossi, ; De Bock et al.

This aligns with the proliferative nature of ECs. This is due to a decrease in the ability of the ECs to metabolize glucose through glycolysis, indicating again the importance of PFKB3 in the regulation of glycolysis in proliferating cells.

Together, these bodies of evidence make PFKFB3 an interesting target of the Warburg effect, and further research should be done in understanding its role in the maturing and differentiating cardiomyocyte. As previously described, high levels of anabolic metabolism and the biosynthesis of cellular content are required for rapidly dividing and proliferating cells.

This PPP is critical in this process. G6PD temporarily shunts glucose from the glycolytic pathway to the PPP, where it leads to the production of ribose and NADPH.

These products are critical for biosynthesis and anabolic metabolism. As described by Yang et al. Knockdown of G6PD decreases cancer cell proliferation and glycolysis, while reducing the tumorigenic properties of gastric cancer cells Deng et al.

In non-cancerous cells, reduced G6PD activity blocks regular proliferation and can lead to deficiencies in growth and development in animal models Tian et al. The mammalian knockout of G6PD leads to embryonic lethality Longo, Increasing PPP activity has been associated with increased and more aggressive tumor malignancy Richardson et al.

G6PD is also regulated through transcription, translation, post-translational modification, as well as numerous positive and negative regulators Stanton, However, a detailed description of these regulations is beyond the scope of this review.

Importantly, along with leading to the production of important components for proliferation, NADPH is essential in protecting cells from oxidative stress as described by Yang et al.

Briefly, NADPH is a potent antioxidant, and the knockout of G6PD leaves embryonic stem cells highly sensitized to oxidants, such as diamide, ultimately resulting in increased cell death Pandolfi et al.

NADPH is essential to the proper functioning of the major components of the antioxidant system, the glutathione system, catalase, and superoxide dismutase, either through NAPDHs reductive properties, or through allosteric binding Zhang et al. Indeed, in hypertrophied cardiomyocytes, there is a decrease in G6PD expression Li et al.

Moreover, restoring G6PD activity prevents the dysregulation of mitochondrial function and oxidative stress experienced by these cells Li et al. This indicates the importance of G6PD in adult cardiomyocytes.

Of note, this seems to be at odds with the high activity of G6PD also seen in proliferative cancer cells. Considering that differentiated cells seem to have almost opposite metabolic profiles compared to proliferating cells, further research needs to be done looking at the role of G6PD in cardiomyocyte development and differentiation.

Mitochondrial fatty acid oxidation plays an important role in cardiomyocyte maturation. A dramatic increase in fatty acid oxidation occurs in the maturing heart following birth Lopaschuk et al.

Interestingly, a decrease in fatty acid oxidation is seen in the stressed heart, such as that seen with congenital heart defects, which maintains a more fetal metabolic and contractile phenotype Lopaschuk et al. In the transition from the fetal to newborn period, there are significant changes in energy metabolism Lopaschuk et al.

Fatty acid oxidation is low in the fetal heart as a result of the low levels of fatty acids present Girard et al.

In the newborn period, there is a shift in the metabolic profile to sustain the cellular growth that occurs during this period Soonpaa et al. This includes a shift toward increased fatty acid oxidation, which produces the majority of ATP in the newborn and supports the increased requirement for ATP from the rapidly growing and beating heart Lopaschuk et al.

PPARα forms heterodimers with retinoid X receptor RXR , which regulates the expression of genes involved in fatty acid activation van der Lee et al.

Mitochondrial fatty acid uptake is necessary for fatty acid oxidation, and this uptake is mediated by CPT-1 Lopaschuk et al. CPT1 is regulated through the inhibitory effects of malonyl-CoA, which is a key regulator of cardiac fatty acid oxidation Lopaschuk et al.

Malonyl-CoA levels are also a key regulator of fatty acid oxidation in the newborn period, with levels decreasing rapidly in the days after birth Lopaschuk et al. Reduced levels of malonyl-CoA occur due to both a decrease in synthesis and an increase in degradation Lopaschuk et al.

Malonyl-CoA synthesis is catalyzed by acetyl-CoA carboxylase ACC , an enzyme which is phosphorylated and subsequently inactivated after birth by AMPK Hardie, ; Hardie, ; Saddik et al. AMPK also acts as an activator of PGC-1α, which also leads to an increase in fatty acid oxidation Jager et al.

Malonyl-CoA is also reduced due to its degradation through decarboxylation by Malonyl-CoA decarboxylase MCD Dyck et al. MCD expression is high in the neonatal heart which, along with the inhibition of ACC, leads to a decrease in malonyl-CoA and an increase in fatty acid oxidation Sakamoto et al.

Evidence suggests that hiPSC-CMs do not display adult cardiomyocyte metabolism, but rather maintain more fetal cardiomyocyte characteristics Mummery et al.

However, incubating hiPSC-CMS with fatty acid increases maturation, as seen through improvements in morphology, protein expression, and metabolism particularly through an increase in fatty acid oxidation Drawnel et al.

During the maturation of hiPSC-CMs, PGC-1α is a major upstream regulator, which is a known transcriptional regulator of fatty acid oxidation Venkatesh et al. This increase in fatty acid oxidation was further evidenced by an overexpression of PDK4, which inhibits PDH activity, and an increased expression of PGC-1α, which leads to an increase in ATP production through fatty acid oxidation Miao et al.

The role of ketone oxidation in the regulation of cell fate has not been extensively studied. However, emerging evidence suggest a key role for ketones in the regulation of cell fate, such as in cancer Singh et al.

The increased presence of ketone bodies in the immediate postnatal period also lends to the potential role it may have in regulating cardiomyocyte fate.

Ketogenic diets KD use a high-fat and low-carbohydrate diet to increase levels of circulating ketone bodies, the main ketone in humans being ß-hydroxybutyrate βOHB.

βOHB has been shown to have an anti-tumor affect in tumor models, through the regulation of the immune system Ferrere et al. The KD has also been shown to decrease tumor proliferation by decreasing rates of glycolysis Singh et al.

It should also be noted that the KD leads to increased mitochondrial enzymes and protein content, as well as increased fatty acid oxidation Sparks et al. Studies on neurodegenerative disorders have found that treatment with KD leads to a PGC-1α regulated increase in mitochondrial biogenesis Hasan-Olive et al.

This provides evidence that the KD can manipulate the mitochondria, the regulation of which plays a large role in determining cell fate. Additionally, in the immediate newborn period, there is an increase in circulating ketones which provides an additional metabolic substrate during this time of cellular development.

Bougneres et al. βOHB is not only a fuel source for the heart but also has cell signaling properties. One signaling pathway involves the endogenous inhibition of histone deacetylases HDAC Newman and Verdin, HDACs alter gene expression through the regulation of chromatin structure.

HDAC2 knockout and knockdown studies in animals and cell cultures are known to increase differentiation and reduce proliferation of cancerous cells Jurkin et al. HDAC2 knockdown is associated with upregulation of cyclin-dependent kinase inhibitors, p21 and p27, which are important enzymes in the regulation of the cell cycle Jurkin et al.

βOHB specifically seems to inhibit HDAC2 by increasing histone p21 gene expression Mierziak et al. In hypertrophied cardiomyocytes, gene expression and metabolism are similar to fetal cells, as seen by an increased reliance on glycolytic metabolism Razeghi et al. HDAC2 plays a role in the regulation of many fetal cardiac isoforms in cardiomyocytes, as seen in cardiac hypertrophy studies Trivedi et al.

The inhibition of HDAC2 may prevent this shift toward a Warburg-like metabolic state seen in hypertrophied cardiomyocytes Trivedi et al. As such, βOHB may play a role in the maturation of cardiomyocytes through its regulation of HDAC2. Given the significant changes that occur in the postnatal period and the evidence regarding the KDs effect on diseased states through regulation of metabolism, ketones and their oxidation may play a role in the regulation of cell fate Figure 2.

Given the combined body of evidence, the involvement of ketones in cell maturation warrants further study. In addition to fatty acids, carbohydrates, and ketones, amino acids are also a potential source of carbons for mitochondrial oxidative metabolism.

The most prevalent of these amino acids is glutamine. Of importance, alterations in mitochondrial glutamine metabolism have been implicated in mediating cell fate.

Although little is known regarding glutamine metabolism in maturing cardiomyocyte, glutamine metabolism does increase in tumor cells and is associated with an increase in cell proliferation Kovačević, ; DeBerardinis and Cheng, Similar to glycolysis, glutamine metabolism seems to be favored in cancer cells due to its contribution toward anabolic metabolism.

Glutamine is a nitrogen donor in the process of nucleotide biosynthesis and, as discussed previously, is key for maintaining the cellular content for the rapidly proliferating cell Ahluwalia et al. Glutamine metabolism is also a source of NADPH, which is required for anabolic processes Vander Heiden et al.

Glutamine, after being converted to glutamate, is also able to replenish the mitochondrial TCA cycle carbon pool anaplerosis , through its deamination into α-ketoglutarate α-KG , replenishing oxaloacetate OAA which provides precursors for the synthesis of nucleotides, proteins, and lipids DeBerardinis et al.

In cancerous cells, citrate is formed through glutamine-dependent reductive carboxylation, as opposed to oxidative metabolism DeBerardinis et al. When cells are starved of glutamine, supplementation with α-KG promotes reductive metabolism, whereas OAA and pyruvate promotes oxidative metabolism Fendt et al.

α-KG produces isocitrate, citrate and acetyl-CoA, which are important for cellular biosynthesis, indicating the importance of glutamine-derived α-KG Dyer et al.

In vitro cell lines consume ten-fold greater amounts of glutamine compared to the consumption of other amino acids Eagle, As such, several studies have looked at inhibiting glutamine metabolism as an anti-cancer target.

It has also been shown that glutamine-derived α-KG is essential for the survivability of hiPSCs Tohyama et al. Beyond anaplerosis, glutamine is also important in the synthesis of glutathione, which, as discussed previously, is cardioprotective through its antioxidative effects Jain et al.

Therefore, it is possible that mitochondrial glutamine metabolism plays a role in the fate of other proliferating cells, such as the fetal cardiomyocyte, and that changes in glutamine metabolism are present in the differentiating and maturing cardiomyocyte Figure 2.

Changes in mitochondrial dynamics and homeostasis, as well as changes in mitochondrial energy metabolism, have a critical role in determining cell fate. Studies in fetal cardiomyocytes, cancer cells, and stem cells have provided a better understanding of how mitochondrial function and energy metabolism affect cell proliferation and differentiation.

It is clear that proliferating cells rely mainly on glycolysis for energy production and its contribution to anabolic metabolism, resulting in a high Warburg effect. What is not clear is the mechanism which controls this Warburg effect, particularly in immature cardiomyocytes.

These changes in energy metabolism are paralleled by changes in mitochondrial dynamics and homeostasis, and a shift from increased fission and mitophagy in the proliferating state to an increase in fusion and mitochondrial biogenesis.

Given the importance of changes in energy metabolism seen during this transition, the role the metabolism of other substrates, such as ketones and glutamine, have in cell fate requires further research. This understanding will be particularly important for understanding the fetal to newborn changes in the physiology and functioning of the heart, as well for applications in regenerative medicine.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abdel-Haleem, A. The Emerging Facets of Non-cancerous Warburg Effect. PubMed Abstract CrossRef Full Text Google Scholar. Abel, D. Mitochondrial Dynamics and Metabolic Regulation in Cardiac and Skeletal Muscle. Clincal Climatol. Google Scholar. Adaniya, S. Posttranslational Modifications of Mitochondrial Fission and Fusion Proteins in Cardiac Physiology and Pathophysiology.

Physiology-Cell Physiology 5 , C—C CrossRef Full Text Google Scholar. Agathocleous, M. Metabolic Differentiation in the Embryonic Retina. Ahluwalia, G. Metabolism and Action of Amino Acid Analog Anti-cancer Agents. Ahn, C. Mitochondria as Biosynthetic Factories for Cancer Proliferation.

Cancer Metab. Ahuja, P. Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration. Allen, L.

Advances in the Surgical Treatment of Heart Failure. Anastasiou, D. Pyruvate Kinase M2 Activators Promote Tetramer Formation and Suppress Tumorigenesis. Ashizawa, K. In Vivo Regulation of Monomer-Tetramer Conversion of Pyruvate Kinase Subtype M2 by Glucose Is Mediated via Fructose 1,6-Bisphosphate.

Attardi, G. Biogenesis of Mitochondria. Baker, M. Mitochondrial Protein-Import Machinery: Correlating Structure with Function. Trends Cell. Bhandari, P. Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and its Containment by Suppressing Mitofusin.

Boroughs, L. Metabolic Pathways Promoting Cancer Cell Survival and Growth. Bougneres, P. Ketone Body Transport in the Human Neonate and Infant. Bracha, A. Carbon Metabolism-Mediated Myogenic Differentiation. Brandt, J. Fatty Acids Activate Transcription of the Muscle Carnitine Palmitoyltransferase I Gene in Cardiac Myocytes via the Peroxisome Proliferator-Activated Receptor α.

Braunwald, E. The War against Heart Failure: The Lancet Lecture. Lancet , — Chen, C. Coordinated Changes of Mitochondrial Biogenesis and Antioxidant Enzymes during Osteogenic Differentiation of Human Mesenchymal Stem Cells.

Stem Cells 26 4 , — TSC-mTOR Maintains Quiescence and Function of Hematopoietic Stem Cells by Repressing Mitochondrial Biogenesis and Reactive Oxygen Species. Chen, H. Emerging Functions of Mammalian Mitochondrial Fusion and Fission. Chen, L. Positive Feedback Loop between Mitochondrial Fission and Notch Signaling Promotes Survivin-Mediated Survival of TNBC Cells.

Death Dis. Chen, M. Mitophagy Receptor FUNDC1 Regulates Mitochondrial Dynamics and Mitophagy. Autophagy 12 4 , — Chen, Y. Mitochondrial Fusion Is Essential for Organelle Function and Cardiac Homeostasis. Chesney, J. An Inducible Gene Product for 6-PhosphofructoKinase with an Au-Rich Instability Element: Role in Tumor Cell Glycolysis and the Warburg Effect.

Cho, Y. Dynamic Changes in Mitochondrial Biogenesis and Antioxidant Enzymes during the Spontaneous Differentiation of Human Embryonic Stem Cells.

Biophysical Res. Christofk, H. The M2 Splice Isoform of Pyruvate Kinase Is Important for Cancer Metabolism and Tumour Growth. Nature , — Pyruvate Kinase M2 Is a Phosphotyrosine-Binding Protein.

Chung, S. Mitochondrial Oxidative Metabolism Is Required for the Cardiac Differentiation of Stem Cells. Cieślar-Pobuda, A. The Expression Pattern of PFKFB3 Enzyme Distinguishes between Induced-Pluripotent Stem Cells and Cancer Stem Cells.

Oncotarget 6 30 , — Civiletto, G. OPA1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models. Clem, B. Small-Molecule Inhibition of 6-PhosphofructoKinase Activity Suppresses Glycolytic Flux and Tumor Growth. Cancer Therap. Cogliati, S.

Mitochondrial Cristae: Where Beauty Meets Functionality. Trends Biochem. Cowie, M. The Epidemiology of Heart Failure. Heart J. Csiszar, A. Resveratrol Induces Mitochondrial Biogenesis in Endothelial Cells. Physiology-Heart Circulatory Physiology 1 , H13—H Dai, D.

Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes. Stem Cells Int. Dean, M. Tumour Stem Cells and Drug Resistance. Cancer 5 4 , — DeBerardinis, R.

Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer. Oncogene 29 3 , — The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation. Beyond Aerobic Glycolysis: Transformed Cells Can Engage in Glutamine Metabolism that Exceeds the Requirement for Protein and Nucleotide Synthesis.

Deng, P. Desai, S. Regulation of Mitophagy by the Ubiquitin Pathway in Neurodegenerative Diseases. Maywood 6 , — De Bock, K.

Role of PFKFB3-Driven Glycolysis in Vessel Sprouting. Ding, L. Involvement of P38mapk and Reactive Oxygen Species in Icariin-Induced Cardiomyocyte Differentiation of Murine Embryonic Stem Cells In Vitro. Stem Cells Dev. Dobrina, A.

Metabolic Properties of Freshly Isolated Bovine Endothelial Cells. Biochimica Biophysica Acta BBA - Mol. Drawnel, F. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy Using Human Induced Pluripotent Stem Cells.

Dyck, J. Characterization of Cardiac Malonyl-COA Decarboxylase and its Putative Role in Regulating Fatty Acid Oxidation. Physiology-Heart Circulatory Physiology 6 , H—H Characterization of Rat Liver Malonyl-COA Decarboxylase and the Study of its Role in Regulating Fatty Acid Metabolism. Dyer, A.

Antagonism of Glycolysis and Reductive Carboxylation of Glutamine Potentiates Activity of Oncolytic Adenoviruses in Cancer Cells. Cancer Res.

Eagle, H. Nutrition Needs of Mammalian Cells in Tissue Culture. Science , — Egbuche, O. Contemporary Pharmacologic Management of Heart Failure with Reduced Ejection Fraction: A Review.

Ccr 16 1 , 55— Elgass, K. Recent Advances into the Understanding of Mitochondrial Fission. Fendt, S. Reductive Glutamine Metabolism Is a Function of the α-ketoglutarate to Citrate Ratio in Cells.

Feng, X. The Involvement of Mitochondrial Fission in Maintenance of the Stemness of Bone Marrow Mesenchymal Stem Cells. Maywood 1 , 64— Ferrere, G. Ketogenic Diet and Ketone Bodies Enhance the Anticancer Effects of PD-1 Blockade. JCI Insight 6 2 , e Fillmore, N.

Effect of Fatty Acids on Human Bone Marrow Mesenchymal Stem Cell Energy Metabolism and Survival. PLOS ONE 10 3 , e Finck, B. The PPAR Regulatory System in Cardiac Physiology and Disease.

Folmes, C. Metabolic Plasticity in Stem Cell Homeostasis and Differentiation. Stem Cell. Energy Metabolism Plasticity Enables STEMNESS Programs.

Somatic Oxidative Bioenergetics Transitions into Pluripotency-dependent Glycolysis to Facilitate Nuclear Reprogramming. Forni, M. Murine Mesenchymal Stem Cell Commitment to Differentiation Is Regulated by Mitochondrial Dynamics. Stem Cells 34, — Fröhlich, C. Structural Insights into Oligomerization and Mitochondrial Remodelling of Dynamin 1-like Protein.

Embo J. Fu, W. Mitochondrial Dynamics: Biogenesis, Fission, Fusion, and Mitophagy in the Regulation of Stem Cell Behaviors. Fujiwara, M. The Mitophagy Receptor Bcllike Protein 13 Stimulates Adipogenesis by Regulating Mitochondrial Oxidative Phosphorylation and Apoptosis in Mice.

Fukushima, A. Acetylation Contributes to Hypertrophy-Caused Maturational Delay of Cardiac Energy Metabolism. JCI Insight 3 10 , e Garbern, J.

Mitochondria and Metabolic Transitions in Cardiomyocytes: Lessons from Development for Stem Cell-Derived Cardiomyocytes. Garnett, M. Pyruvate Kinase Isozyme Changes in Parenchymal Cells of Regenerating Rat Liver. Gegg, M. Gilde, A.

Circulation Res. Gilkerson, R. The Cristal Membrane of Mitochondria Is the Principal Site of Oxidative Phosphorylation. FEBS Lett. Girard, J. Adaptations of Glucose and Fatty Acid Metabolism during Perinatal Period and Suckling-Weaning Transition. Gleyzer, N. Control of Mitochondrial Transcription Specificity Factors TFB1M and TFB2M by Nuclear Respiratory Factors NRF-1 and NRF-2 and PGC-1 Family Coactivators.

Gong, G. Mitochondrial Flash as a Novel Biomarker of Mitochondrial Respiration in the Heart. Physiology-Heart Circulatory Physiology , H—H Parkin-Mediated Mitophagy Directs Perinatal Cardiac Metabolic Maturation in Mice.

Science , Gulick, T. The Peroxisome Proliferator-Activated Receptor Regulates Mitochondrial Fatty Acid Oxidative Enzyme Gene Expression. Hansson, J. Highly Coordinated Proteome Dynamics during Reprogramming of Somatic Cells to Pluripotency.

Hardie, D. Regulation of Fatty Acid and Cholesterol Metabolism by the AMP-Activated Protein Kinase. Biochimica Biophysica Acta BBA - Lipids Lipid Metabolism 3 , — Regulation of Fatty Acid Synthesis via Phosphorylation of Acetyl-COA Carboxylase. Lipid Res.

This outer portion includes proteins called porins, which form channels that allow proteins to cross. The outer membrane also hosts a number of enzymes with a wide variety of functions. Inner membrane: This membrane holds proteins that have several roles.

Because there are no porins in the inner membrane, it is impermeable to most molecules. Molecules can only cross the inner membrane in special membrane transporters. The inner membrane is where most ATP is created. Cristae: These are the folds of the inner membrane.

They increase the surface area of the membrane, therefore increasing the space available for chemical reactions. Matrix: This is the space within the inner membrane. Containing hundreds of enzymes, it is important in the production of ATP.

Mitochondrial DNA is housed here see below. Different cell types have different numbers of mitochondria. For instance, mature red blood cells have none at all, whereas liver cells can have more than 2, Cells with a high demand for energy tend to have greater numbers of mitochondria.

Around 40 percent of the cytoplasm in heart muscle cells is taken up by mitochondria. Although mitochondria are often drawn as oval-shaped organelles, they are constantly dividing fission and bonding together fusion. So, in reality, these organelles are linked together in ever-changing networks.

Also, in sperm cells, the mitochondria are spiraled in the midpiece and provide energy for tail motion. Although most of our DNA is kept in the nucleus of each cell, mitochondria have their own set of DNA. Interestingly, mitochondrial DNA mtDNA is more similar to bacterial DNA.

The mtDNA holds the instructions for a number of proteins and other cellular support equipment across 37 genes. The human genome stored in the nuclei of our cells contains around 3. However, the child always receives their mtDNA from their mother. Because of this, mtDNA has proven very useful for tracing genetic lines.

For instance, mtDNA analyses have concluded that humans may have originated in Africa relatively recently, around , years ago, descended from a common ancestor, known as mitochondrial Eve.

Although the best-known role of mitochondria is energy production, they carry out other important tasks as well. In fact, only about 3 percent of the genes needed to make a mitochondrion go into its energy production equipment.

The vast majority are involved in other jobs that are specific to the cell type where they are found. ATP, a complex organic chemical found in all forms of life, is often referred to as the molecular unit of currency because it powers metabolic processes. Most ATP is produced in mitochondria through a series of reactions, known as the citric acid cycle or the Krebs cycle.

Mitochondria convert chemical energy from the food we eat into an energy form that the cell can use. This process is called oxidative phosphorylation. The Krebs cycle produces a chemical called NADH.

NADH is used by enzymes embedded in the cristae to produce ATP. In molecules of ATP, energy is stored in the form of chemical bonds. When these chemical bonds are broken, the energy can be used. Cell death, also called apoptosis, is an essential part of life.

As cells become old or broken, they are cleared away and destroyed. Mitochondria help decide which cells are destroyed. Mitochondria release cytochrome C, which activates caspase, one of the chief enzymes involved in destroying cells during apoptosis.

Because certain diseases, such as cancer , involve a breakdown in normal apoptosis, mitochondria are thought to play a role in the disease. Calcium is vital for a number of cellular processes. MitoT can occur and treat different diseases through the formation of tunnelling nanotubes TNTs , gap junctions GJs , formation of extracellular vesicles EVs , cell fusion, etc.

Table 1. Among them, TNTs are the most common mode to transfer mitochondria. For instance, Jiang et al. reported that MitoT is a ubiquitous inter-cellular transfer mechanism between BMSCs and a variety of ocular cells, such as corneal endothelial cells, retinal pigment epithelial cell lines, and photoreceptor cell lines, and is dependent upon F-actin-based TNTs [ 35 ].

Jackson et al. observed that mitochondria transferred from the BMSCs, partially through TNTs, could enhance the phagocytosis of the macrophages in mouse models and thereby ameliorate acute respiratory distress syndrome ARDS and sepsis [ 36 ].

In addition, the BMSCs could protect target organs from apoptosis through a mitochondrial transfer of TNTs and play a role in the treatment of acute lymphoblastic leukaemia ALL. Lastly, Luz-Crawford et al. Further, the mitochondrial transfer to the Th17 cells was impaired when co-culturing with human synovial MSCs sMSCs from patients with rheumatoid arthritis RA when compared with healthy BMSCs; in addition, this artificial MitoT also significantly reduced the IL production in the Th17 cells, suggesting that a reduced mitochondrial transfer by the RA-sMSCs may be the main reason for the persistence of chronic inflammation in RA synovitis [ 38 ].

MitoT can also occur through GJs. Islam et al. reported that gap junctional channels can be formed between the BMSCs and injured alveolar epithelial cells, to facilitate the transfer of mitochondrial-encapsulated vesicles into the alveolar epithelial cells; these vesicles are then ingested by endocytosis to treat acute lung injury [ 39 ].

Recent studies have also reported that the role of MSCs is mainly due to the transfer of EVs. EVs are able to transfer a variety of substances, including organelles such as mitochondria, and are thus considered a more feasible candidate for therapy than whole-cell delivery.

Further, the BMSCs can promote the anti-inflammatory function of alveolar macrophages in an ARDS environment through the mitochondrial transfer mediated by EVs; this stimulates the expression of the macrophage phenotype that shows high phagocytosis.

Further, the BMSC-derived EVs can also reduce inflammation and lung injury in lipopolysaccharide-injured mice in vivo [ 41 ]. Finally, the mitochondria in the MSCs can also be transferred to recipient cells by cell fusion.

For example, adipose-derived mesenchymal stem cells AD-MSCs co-cultured with cardiomyocytes can transfer mitochondria by cell fusion, and then reprogram the adult cardiac cells towards a progenitor-like state to achieve therapeutic effects [ 42 ].

In addition, the MSCs derived from different tissue sources show differences in mitochondrial respiration, donor capacity, and therapeutic effects. For instance, the BMSCs and AD-MSCs have obvious mitochondrial transfer characteristics, while dental pulp stem cells and umbilical cord-derived mesenchymal stem cells UCMSCs have apparent aerobic respiratory capacities; subsequently, they transfer the same number of mitochondria and show effective therapeutic effects [ 20 ].

In general, the MSCs can transfer mitochondria through various modes to restore the mitochondrial functions in the target cells to rescue the target organ damage, such as an ocular tissue injury, lung injury, and myocardial injury, and play an important role in immune regulation.

Lastly, the mitochondria isolated from MSCs can be directly introduced into injured tissues as drugs to mimic the mitochondrial transfer in vivo; this may be a new treatment for diseases and thus warrants the need for future studies [ 43 ].

Mitochondrial biogenesis is controlled by PGC-1α that further activates the expression of nuclear respiration factors Nrf1 and Nrf2 and oestrogen-related receptor-α ERR-α , which activate mitochondrial transcription factor A TFAM to coordinate with the DNA polymerase γ and promote mtDNA replication [ 44 ].

In addition, Nrf1, Nrf2, and ERR-α can also bind to promoter regions of nuclear genes which encode the subunits of five complexes Complex I-V in mitochondrial electron transport chain ETC , thereby regulating mtDNA replication [ 45 ]. During the differentiation of the MSCs, the biogenesis of mitochondria increases, leading to an increase in the number of mitochondria in the differentiated cells.

For example, after an osteogenic induction of the BMSCs, the levels of proteins involved in mitochondrial biogenesis, such as PGC-1α, TFAM, DNA polymerase γ, and protein subunits of Complex III-V in ETC, increase as well [ 46 ].

Moreover, during an adipogenic differentiation of the BMSCs, the expression level of the outer mitochondrial membrane protein, TOM20, increases significantly along with the increase in the number of mitochondria as confirmed via staining [ 24 ]. In addition, during the differentiation of the BMSCs into hepatocytes, the expression of several mitochondrial proteins and biogenesis regulators increases as well, such as PGC-1α; OXPHOS activity, capacity, and efficiency; ratio of mitochondria to cytoplasm; and the mtDNA content in the differentiated cells [ 47 ].

Similarly, an osteogenic differentiation of the BMSCs and UCMSCs is accompanied by mitochondrial biogenesis that is characterised by an increase in the expression of regulatory factors that induce mitochondrial biogenesis, mtDNA copy number, cristae development, and expression and activity of the OXPHOS complex [ 19 ].

In summary, these studies indicate that the differentiation of the MSCs is often accompanied by mitochondrial biogenesis which is regulated by PGC-1α; and caused glycolysis weakened and OXPHOS enhanced, in turn generating enough energy to meet the metabolic needs of the MSCs Fig.

The role of mitochondrial biogenesis in the differentiation of MSCs. The biogenesis of mitochondria is controlled by PGC-1α, followed by the activation of Nrf1, Nrf2, and ERR-α, then activates TFAM, which coordinates with the DNA polymerase γ, thus promoting mitochondrial DNA replication.

And Nrf1, Nrf2, and ERR-α also activate the Complex I-V in ETC, thus promoting mitochondrial DNA replication. The activation of mitochondrial biogenesis leads to glycolysis weakened and OXPHOS enhanced, which give rise to the osteogenic and adipogenic differentiation of MSCs.

ERR-α, Oestrogen-related receptor-α. ETC, Electron transport chain. MSCs, Mesenchymal stem cells. Nrf1, Nuclear respiration factor 1.

Nrf2, Nuclear respiration factor 2. OXPHOS, Oxidative phosphorylation. PGC-1α, PPARγ coactivator-1α. TFAM, Mitochondrial transcription factor A.

Mitochondrial dynamics mainly include the fusion and fission of the mitochondria and mostly depend upon the biological processes, such as apoptosis, calcium homeostasis, and ATP production [ 14 ]. Mitochondrial fusion includes the fusion of the inner mitochondrial membrane IMM and outer mitochondrial membrane OMM.

The dynamic protein-related GTPases, mitofusin 1 and 2 MFN1 and MFN2, respectively , mediate the fusion of the OMM, while optic atrophy 1 OPA1 and MFN1 mediate the fusion of the IMM. Some other proteins also participate in mitochondrial fusion, including prohibitin that regulates OPA1 [ 48 ].

In contrast, the mitochondrial fission is mainly regulated by the dynamin-related protein 1 DRP1 that induces mitochondrial contraction and fission when receptors, such as mitochondrial fission factor MFF , Fission 1 FIS1 , and Fission 2 FIS2 , are recruited to the OMM.

Moreover, multiple post-translational modifications are also involved in the regulation of the mitochondrial dynamics [ 49 , 50 ]. During the differentiation of the MSCs, the mitochondrial dynamics change; for instance, Forni et al. reported that in the early stage of adipogenic and osteogenic differentiation, the content of citrate synthase in mouse MSCs significantly increases, MFN1 and MFN2 are upregulated, and the mitochondria elongate; these indicate the occurrence of mitochondrial fusion during adipogenesis and osteogenesis.

Furthermore, during chondrogenesis, the expression of DRP1 , FIS1 , and FIS2 increases; the knockout of these genes results in the loss of the chondrogenic differentiation ability of the MSCs in mice [ 30 ]. Moreover, melatonin can promote the mitochondrial dynamics and metabolism of the BMSCs, enhance the functions of the mitochondria, and protect the BMSCs from excessive ageing in mice with chronic kidney disease [ 51 ].

Further, the mitochondrial dynamics of amniotic membrane-derived MSCs can affect the immune regulatory function of the MSCs [ 52 ]. In conclusion, the above studies suggest that the mitochondrial dynamics play a critical role in regulating the multi-directional differentiation, ageing, and immune regulation of MSCs via different mechanism Fig.

The role of mitochondrial dynamics in the function regulation of MSCs. Mitochondrial fusion is activated during the adipogenic and osteogenic differentiation, and immune regulation of the MSCs. The process of mitochondrial fusion involves the fusion of OMM and IMM.

MFN1 and MFN2 mediate the fusion of the OMM, while the OPA1 protein and MFN1 mediate the fusion of the IMM. Moreover, mitochondrial fission is enhanced during the chondrogenic differentiation and immune regulation of the MSCs and protects the MSCs against ageing.

And DRP1 regulates the mitochondrial fission, and the receptors, such as MFF, FIS1, and FIS2, are recruited into the OMM and induce mitochondrial contraction and fission. DRP1, Dynamin-related protein 1.

FIS1, Fission 1. FIS2, Fission 2. IMM, Inner mitochondrial membrane. MFF, Mitochondrial fission factor. MFN1, Mitofusin 1. MFN2, Mitofusin 2.

OMM, Outer mitochondrial membrane. OPA1, Optic atrophy 1. Mitophagy is a process in which mitochondrial membrane depolarisation stabilises PTEN-induced kinase 1 PINK1 on the OMM during mitochondrial stress or injury. PINK1 accumulates on the OMM through the translocase of the outer membrane TOM , which leads to the recruitment of E3 ubiquitin ligase Parkin through the PINK1-dependent phosphorylation and a subsequent formation of mitochondrial phagosomes [ 53 , 54 ].

The purpose of mitophagy in the MSCs is to eliminate the damaged or dysfunctional mitochondria and control their number [ 55 ]. While under normal conditions, PINK1 is continuously targeted to the mitochondria through a mitochondrial targeting sequence, degraded by matrix processing peptidases MPP and subsequently cleaved by presenilin-associated rhomboid like PARL , a protease in the mitochondrial inner membrane.

Cleaved PINK translocates to the cytosol and is degraded by the proteasome [ 56 ]. Nuschke et al. reported that the accumulation of LC3-II protein, a marker of mitophagy activation, is associated with osteogenic differentiation; this suggests that mitophagy is activated during BMSC differentiation [ 57 ].

Consistent with this conclusion, Song et al. also reported that the BMSCs promoted adipogenic differentiation through mitophagy. The addition of mitophagy inhibitors, chloroquine and 3-methyladenine, could inhibit the adipogenic differentiation of the BMSCs, indicating that MSC differentiation is closely related to mitophagy as well [ 58 ].

In some diseases and in the ageing process, the accumulation of damaged mitochondria can lead to the deterioration of the stem cell properties. When dysfunctional mitochondria accumulate in the MSCs and do not undergo mitophagy, they may directly affect the activity and function of the stem cells and hinder tissue renewal and regeneration [ 59 ].

In addition, the reduction of BCL2-associated athanogene 5 BAG5 , a direct target of miRp the most important miRNA in inflammation and ageing tissues , can lead to the dysregulation of PINK1, and thereby destroy the mitophagy of the BMSCs and lead to cell ageing [ 60 ]. Therefore, mitophagy is regulated by PINK1-Parkin pathway and activated during MSC osteogenic and adipogenic differentiation, and the restoration of the mitophagy function of the damaged mitochondria is essential to maintain the multi-directional differentiation and self-renewal and inhibit ageing in the MSCs Fig.

The role of mitophagy in the function regulation of MSCs. During mitochondrial stress or injury, PINK1 accumulates on the OMM through TOM, which leads to Parkin recruitment through PINK1-dependent phosphorylation, subsequently caused the formation of mitochondrial phagosomes, and finally induces the mitophagy.

Mitophagy is activated during MSC osteogenic and adipogenic differentiation, which is essential to inhibit ageing in MSCs, while PINK1 is degraded by MPP and subsequently cleaved by PARL. And BAG5 can maintain the function of PINK1.

BAG5, BCL2 associated athanogene 5. MPP, Matrix processing peptidases. PARL, Presenilin-associated rhomboid like. PINK1, PTEN-induced kinase 1.

TOM, Translocase of the outer membrane. Most studies have reported that stem cells mainly rely on glycolysis for metabolism [ 13 ]. This may be because higher glycolysis rates coupled with reduced OXPHOS are necessary for the MSCs to provide the co-factors and substrates of the biosynthetic reactions required for their proliferation [ 14 ].

In addition, anaerobic metabolism may help in avoiding oxidative damage caused by the ROS produced by mitochondria, and avoid damage to the genetic material and cellular components [ 61 ]. Meanwhile, the MSCs have also been considered to rely on anaerobic energy metabolism because they are always isolated from the source tissues in a hypoxic microenvironment, and their dependence on glycolysis may be a long-term evolutionary adaptation of the stem cells to their hypoxic niche.

In addition, the MSCs in damaged tissues or transplanted MSCs are usually exposed to hypoxic environments; this interferes with the aerobic metabolism in cells, and consequently, they utilise anaerobic glycolysis to provide most of the energy required for the cellular functions [ 46 ].

This indicates that a hypoxic environment is conducive to glycolytic metabolism and may protect the MSCs from ageing [ 62 ].

Therefore, the MSCs mostly carry out cellular respiration and energy metabolism through glycolysis, perhaps because it is beneficial for their proliferation, helps avoid oxidative damage, or as they are located in a hypoxic niche.

During MSC differentiation, the energy acquisition pathway of the MSCs changes from glycolysis to mitochondrial oxidative metabolism that generates a large amount of energy through mitochondrial OXPHOS to meet the needs of differentiation, while mitochondrial dysfunction impairs this process [ 25 , 30 , 63 ].

The upregulation of mitochondrial biogenesis and aerobic metabolism are characteristics of MSC differentiation [ 46 ]. In undifferentiated BMSCs, HIF-1α, which promotes glycolytic gene expression, is highly expressed, while during the osteogenesis induction of the BMSCs, the HIF-1α gene expression, glycolytic enzyme expression, and lactate production decrease and the oxygen consumption rate OCR and ATP production significantly increase [ 24 , 25 ].

Similarly, the oxygen consumption, mitochondrial biogenesis, and respiratory enzyme complex activity are significantly increased during the adipogenic differentiation of the BMSCs [ 24 , 64 ]. The mitochondrial biogenesis and OCR of mouse skin MSCs msMSCs increases during adipogenesis, suggesting that the undifferentiated MSCs transition from glycolysis to OXPHOS during adipogenic differentiation [ 30 ].

Furthermore, the glycolysis-dependent MSCs require OXPHOS activity for their differentiation [ 65 ]. This indicates that the MSC differentiation is accompanied by an attenuation of glycolysis in mitochondria and the enhancement of the TCA cycle and OXPHOS; moreover, this bioenergy conversion plays a crucial role in the differentiation of MSCs Table 2.

After the addition of an HIF-1 agonist, dimethyloxalylglycine, the ALP gene expression decreases, extracellular acidification rate increases, and OCR decreases; this indicates that the mitochondrial glycolysis was enhanced, and OXPHOS and osteogenic differentiation were inhibited [ 25 ]. Similarly, Shares et al.

Moreover, inducing hypoxia or specific knockout of TFAM, to inhibit the mitochondrial electron transport chain and reduce mitochondrial aerobic respiration, could significantly inhibit the adipogenic differentiation of the BMSCs, indicating that the energy metabolism of mitochondria could regulate the differentiation of the MSCs [ 24 ].

In addition, treating AD-MSCs with mangiferin, a class of flavonoids extracted from mango, could improve the mitochondrial respiratory function by increasing the expression of mitochondrial OCR and OXPHOS-related proteins, thereby inducing the AD-MSCs to differentiate into brown adipocytes and improve obesity [ 67 ].

Rab27b, a member of the small GTPases family, can increase the OXPHOS in cardiac mesenchymal stem cells C-MSCs and significantly reduce mitochondrial glycolysis; consequently, this maintains the fatty acid oxidative metabolism of the C-MSCs, suggesting that regulatory genes and drugs may ultimately play a therapeutic role by affecting the mitochondrial energy metabolism [ 68 ].

However, recent studies have reported that canagliflozin, a therapeutic medicine for type 2 diabetes, can inhibit the activity of glutamate dehydrogenase 1, which interferes with mitochondrial OXPHOS and ATP production; consequently, it inhibits the proliferation and migration of the BMSCs, which may lead to a decline in the tissue repair ability of the transplanted BMSCs.

Thus, some compounds may affect the energy metabolism process of the MSCs and produce secondary actions [ 47 ]. In conclusion, current studies have confirmed that regulatory genes and compounds can induce a transformation of the mitochondrial energy metabolism and regulate the function of the MSCs Table 3.

Moreover, key enzymes that regulate chromatin i. Furthermore, glycolysis and OXPHOS in MSCs are bi-directional and interact with each other; interestingly, the induction of pluripotent stem cells from somatic cells requires a reverse transformation from OXPHOS to glycolysis [ 71 ].

A previous study showed that when inflammation impairs the mitochondrial OXPHOS, it activates intra-cellular glycolysis as a temporary solution to maintain the energy supply [ 72 ].

In general, mitochondrial energy metabolism not only changes the process of stem cell differentiation, but also plays a significant role in the regulation of the stem cell functions.

To conclude, the undifferentiated MSCs are highly dependent on glycolysis for maintenance and self-renewal, while during the initiation of MSC differentiation, the transformation of the metabolic pathways and an upregulation of the mitochondrial functions are essential for a successful differentiation.

Finally, inhibition or promotion of the mitochondrial energy metabolism-related factors can affect the differentiation, proliferation, and migration of the MSCs. A recent study has found that in a long-term culture of human placenta-derived mesenchymal stem cells PD-MSCs , the MMP of the aged PD-MSCs decreased and the mitochondrial volume increased; this indicated that the ageing PD-MSCs had a mitochondrial dysfunction.

The study indicated that carnitine palmitoyltransferase 1A CPT1A , a key rate-limiting enzyme of fatty acid transfer, was overexpressed in the aged PD-MSCs; consequently, an inhibition of CPT1A expression caused changes in the energy metabolism of the PD-MSCs, increased their MMP, and reversed ageing [ 73 ].

Similarly, the apoptosis of the BMSCs induced by decitabine DAC , which plays an important role in cell cycle arrest and cell death induction, is positively correlated with the mitochondrial dysfunction that is caused by a decrease in the MMP. DAC triggers cell damage in a concentration-dependent manner, the greater the concentration of DAC, the more the cell damage.

However, after the addition of a strong antioxidant, N -acetyl- l -cysteine NAC , the MMP was restored by inhibiting the generation of ROS in mitochondria. Thus, as DAC-induced apoptosis can be effectively reversed, it indicates that the MMP may be used as one of the features in determining whether MSC function is impaired [ 27 ].

Other compounds can restore the function of the MSCs by increasing the MMP. For instance, Lee et al. Then, the HSPA1L-PrP C complex binds to COX4IA a mitochondrial complex IV protein , leading to an increase in the MMP and antioxidant enzyme activity. Further, this protects the MSCs against replicative senescence during ex vivo expansion in clinical applications via mitochondrial quality control and MMP [ 74 ].

Meanwhile, the peroxisome proliferator activated receptor γ PPARγ agonist, pioglitazone, alleviates the compression-induced MMP decrease in the nucleus pulposus-mesenchymal stem cells NP-MSCs , protects cell viability, promotes cell proliferation of the NP-MSCs, and alleviates the toxic effects caused by compression [ 75 ].

As the mitochondrial energy metabolism of the MSCs is always accompanied by a change in the MMP Table 4 , their functions may be restored by regulating the changes in the membrane potential to avoid the ageing and apoptosis of the MSCs.

For a long time, ROS have been considered as a cause of cell dysfunction and tissue death due to the destructive oxidation of the intra-cellular components. Excessive ROS can lead to DNA damage, lipid peroxidation, and protein oxidative modification, and thus damage the cell functions [ 46 ].

However, with the rise in studies related to mitochondrial metabolism and dysfunction, people have developed a new understanding of the role of ROS as a signalling molecule.

Previous research has demonstrated that photobiomodulation can promote the migration of the human gingival mesenchymal cells by promoting the activation of mitochondrial ROS and increasing the phosphorylation levels of c-Jun N-terminal kinase and IκB kinase [ 76 ].

In addition, the physiological upregulation of the ROS is necessary for the MSC proliferation, while its inhibition hinders their self-renewal [ 77 ]. Therefore, only an un-regulated level of the ROS is harmful, as their normal physiological level is necessary and beneficial for maintaining the functions of the MSCs [ 78 ].

Unlike their differentiated states, the MSCs in their undifferentiated states have low levels of intra-cellular ROS and high levels of antioxidant enzymes [ 79 ].

Studies have reported that excessive ROS levels can impair the osteogenic differentiation ability of the MSCs [ 68 , 80 ]. However, in the adipogenic differentiation of the MSCs, the production and increase in the ROS levels is not only a result of the adipocyte differentiation, but also one of the conditions for the adipogenic differentiation of the MSCs.

During the adipogenic differentiation of msMSCs, the mitochondrial biogenesis and ROS expression levels are significantly increased. The excessive ROS levels can lead to the activation of a positive feedback of PPARγ, and thereby accelerate the adipogenic differentiation of the msMSCs [ 30 ].

Further, the chondrogenic differentiation of the BMSCs is related to the increase in levels of intra-cellular ROS; however, this may lead to oxidative stress, which is not conducive to cartilage regeneration.

Thus, reducing the levels of ROS may be an effective way to increase the collagen accumulation [ 81 ]. Above all, the ROS levels in the MSCs are different before and after differentiation, and different differentiation directions lead to varying ROS production.

Further, age, long-term culture in vitro, presence of H 2 O 2 , and oxidative stress are major factors that induce MSC senescence. Senescence easily increases the ROS levels, changes mitochondrial morphology, reduces antioxidant capacity, and increases the apoptosis rate; an ROS-mediated oxidative stress-induced replicative senescence can lead to cell membrane lipid peroxidation, mitochondrial dysfunction, energy failure, and metabolic disorders [ 82 ].

Another study has reported that a long-term culture of AD-MSCs to induce replicative senescence can lead to a decrease in their proliferation, cell cycle arrest, and differentiation by inhibiting ROS-induced c-Maf, which is sensitive to oxidative stress [ 83 ].

Moreover, H 2 O 2 is also an important factor leading to oxidative stress-induced premature senescence that has been reported to inhibit the MSC proliferation in a concentration-dependent manner, suggesting that ageing is closely related to ROS production [ 85 ].

Furthermore, in BMSCs with an iron overload, an increase in the ROS levels can lead to the activation of the AMPK kinase complex, trigger mitochondrial division, and ultimately lead to apoptosis [ 86 ].

The above studies indicate that the ROS levels affect the differentiation direction of the MSCs; however, their excessive levels lead to oxidative stress, which may cause mitochondrial dysfunction, apoptosis, and senescence of the MSCs.

To eliminate the increase in the ROS levels and reduce its side effects, some compounds have been found to regulate the ROS levels, and thereby enhance the activities of the MSCs and promote their application in regenerative medicine Table 5. For instance, Chen et al. have reported that a co-culture of rat BMSCs with Mg, in vitro, can reduce oxidative stress injury, increase antioxidant enzyme activity, maintain redox homeostasis, and increase MMP; this reduces the risk of UV-induced apoptosis to treat diseases caused by oxidative stress injury [ 87 ].

The study also reported that 17β-estradiol, an important regulator of energy homeostasis and glucose metabolism, can protect the UCB-MSCs from high glucose-induced mitochondrial ROS production by increasing the nuclear translocation of Nrf2, and thereby protecting the cells from autophagic cell death [ 88 ].

Similarly, the PPARγ agonist, pioglitazone, can suppress the compression-induced oxidative stress in the NP-MSCs; this includes decreasing the compression-induced overproduction of ROS, alleviating compression-induced MPP decrease, and thereby protecting cell viability, cell proliferation, and alleviating the toxic effects caused by compression [ 75 ].

Furthermore, a combined treatment with NAC and l -ascorbic acid 2-phosphate promotes the growth of human AD-MSCs and suppresses the oxidative stress-induced cell death by enhancing mitochondrial integrity and function in vitro [ 89 ].

The above studies suggest that eliminating excessive ROS levels and maintaining the physiological ROS level are essential targets for mitochondrial-related therapy in MSCs. Hypoxia-inducible factor-1 HIF-1 is a heterodimer comprising a structurally stable β-subunit and an active oxygen-regulated α-subunit HIF-1α.

HIF-1α is continuously synthesised and degraded by prolyl hydroxylase under normoxic conditions. As a response to hypoxia, the HIF-1α activation promotes the transition from aerobic respiration to anaerobic glycolysis and inhibits mitochondrial biogenesis [ 90 ].

Mahato et al. Furthermore, most MSCs exist in a hypoxic environment, and such long-term hypoxic conditions upregulate the expression of HIF-1α. When compared with normoxic MSCs, the hypoxic MSCs show higher cell viability, lower ROS levels, and higher resistance to oxidative stress; such hypoxia-induced MSCs alleviate early radiation pneumonia and late pulmonary fibrosis, indicating that HIF-1α plays a key role in regulating the stem cell functions [ 92 ].

Moreover, HIF-1α improves the ability of the BMSCs to reduce inflammation and inhibit pro-inflammatory T cell generation by regulating the metabolic switch from OXPHOS to glycolysis; this suggests that HIF-1α is a vital effector of BMSC-mediated immune therapy [ 93 ].

Meanwhile, the expression of HIF-1α is also important for the quiescence and function of the BMSCs. HIF-1α maintains the expression of pyruvate dehydrogenase kinase, PDK; this prevents the mitochondrial oxidation of acetyl-CoA by inactivating the pyruvate dehydrogenase complex, thus indicating that PDK is beneficial for glycolysis [ 94 ].

Similarly, Hsu et al. found that inhibition of HIF-1α by hypoxia or cobalt chloride in BMSCs can prevent osteogenic differentiation [ 95 ]. In addition, the presence of ascorbic acid, an antioxidant enzyme co-factor, can increase the activity of HIF-1α hydroxylase, inhibit HIF-1α transcription, cause mitochondrial activation, and then promote BMSC proliferation [ 96 ].

In general, HIF-1α inhibits mitochondrial biogenesis and functions, and thus affects the immune regulation, multi-directional differentiation, and proliferation of the MSCs.

PGC-1α is a major regulator of mitochondrial biogenesis, is highly expressed in MSCs when the energy metabolism demand is high, and promotes OXPHOS in the MSCs [ 97 ]. The effect of PGC-1α on the osteogenic and adipogenic differentiation in MSCs is opposite; the overexpression of PGC-1α prevents the osteogenic differentiation potential and increases the adipogenic differentiation potential in the BMSCs [ 98 ].

In addition, during the adipogenic differentiation, the PGC-1α mRNA level increases, mitochondrial mass and mtDNA copy number increase, OXPHOS complex forms, and OXPHOS activity increases; this suggests that an overexpression of PGC-1α can enhance the oxidative metabolism in mitochondria.

Moreover, the inhibition of mitochondrial biogenesis by inhibiting PGC-1α may damage the adipose differentiation potential [ 24 ]. In addition, PGC-1α can induce antioxidant enzymes, such as SOD2, which regulate the ROS levels [ 99 ]. Thus, the above studies indicate that altering the energy metabolism by regulating the expression of PGC-1α could alter the differentiational fate of the MSCs.

Furthermore, the study of PGC-1α will provide a new target for mitochondrial research to improve the mitochondrial activity. SIRT is activated when energy or nutrition is insufficient; this triggers the cellular adaptation and thereby improves the metabolic efficiency [ ].

SIRT1 is the most widely studied sirtuin and it controls the activities of many transcription factors, such as p53, NF-κB, forkhead box O, and sterol regulatory element binding protein.

It is associated with stem cell activation, reprogramming, and autophagy regulation under stress, controls the mitochondrial biogenesis and function, and affects cell senescence [ , ].

Further, SIRT1 knockdown can promote the adipogenic differentiation and inhibit osteogenic differentiation in the BMSCs; this suggests that SIRT1 plays a role in the fate determination of the MSCs [ ].

Meanwhile, SIRT1 can also deacetylate substrates, such as PGC-1α and liver kinase B1 LKB1. It has been reported that SIRT1 can induce phosphorylation of LKB1 through deacetylation, thus regulating AMPK [ ]. In addition, SIRT3, SIRT5, and SIRT7 are also involved in mitochondrial biogenesis and mitochondrial function activation during adipogenic differentiation [ ].

In conclusion, sirtuin can activate mitochondrial biogenesis, improve the metabolic efficiency of mitochondria, and affect the ageing and multi-directional differentiation ability of the MSCs.

SOD2 is a superoxide dismutase that can catalyse the dismutation of superoxide anion radicals to produce O 2 and H 2 O 2. SIRT3 is the main deacetylase that activates SOD2 through deacetylation to reduce the ROS levels and enhance osteogenic differentiation potential of the MSCs [ ].

The low-dose histone deacetylases inhibitor, trichostatin A, can protect the MSCs against oxidative stress through the SOD2 regulation mechanism [ ]. Similarly, the transforming growth factor, TGF-β1, can significantly downregulate the expression of SOD2 and Id1 in the MSCs, and thus increase the levels of the senescence-related genes in a dose-dependent manner [ ].

Furthermore, the BMSC-derived isolated mitochondria could enhance the expression of SOD2 and Bcl-2 and inhibit ROS production in vitro [ ]. In summary, SOD2 can enhance the osteogenic differentiation potential of the MSCs and protect the stem cells from ageing by scavenging the intra-cellular superoxide free radicals and inhibiting ROS production.

AMPK is an energy-sensing kinase and play a crucial role in cell metabolism [ ]. Studies reported that expression and phosphorylation of AMPK are increased during osteogenesis in stem cells from human exfoliated deciduous teeth SHEDs , while after the addition of AMPK inhibitors, compound C, the osteogenic differentiation of AD-MSCs is inhibited and the adipogenic differentiation is promoted, indicating that AMPK is an important molecule regulating the osteogenic and adipogenic differentiation of MSCs [ , ].

LKB1 is an upstream kinase that regulates AMPK, which can be activated by phosphorylation [ ]. Nakada et al. reported that inhibition of LKB1 can reduce the number of mtDNA replication, mitochondrial membrane potential, oxidation capacity, and ATP level in cells and reduce the phosphorylation level of AMPK and the expression of PGC-1α.

In addition, Chen et al. also reported that AMPK can directly activate PGC-1α by phosphorylation of PGC-1α [ ], suggesting that LKB1, AMPK, and PGC-1α are related to each other, which may be one of the signalling pathways regulating the fate of MSCs.

In addition, Mammalian target of rapamycin complex 1 mTORC1 is a downstream target of AMPK. Pantovic et al. Moreover, Tormos et al.

reported that BMSCs treated with rapamycin, an inhibitor of mTORC1, can decrease the OCR and the intra-cellular ROS level during adipogenic differentiation, suggesting that mTORC1 has a positive regulation on ROS [ ].

In summary, AMPK can promote osteogenic differentiation and inhibit adipogenic differentiation of MSCs, which can be activated by LKB1 and reduce ROS level by inhibiting mTORC1. UCP is located in the inner membrane of mitochondria, which is part of the mitochondrial respiratory electron transport chain, and can reduce the proton gradient, thus reducing the electrochemical potential of mitochondria, slowing down the oxidative phosphorylation process driven by proton gradient, thus hindering the normal production of ATP and converting proton driven into heat [ , ].

UCP includes UCP1, UCP2, UCP3, UCP4, and UCP5. UCP1 is considered to be the archetypal uncoupling protein, and which is considered as specific marker of brown adipogenesis and increases respiration, oxygen consumption, dissipates energy, and mitochondrial uncoupled respiration by thermogenesis upon activation [ ].

It has reported that decreased UCP-1 expression in beige adipocytes from AD-MSCs is associated with mitochondrial ROS accumulation during obesity [ ]. Furthermore, during the differentiation of AD-MSCs into brown-like cells, the expression of UCP-1 increased, differentiated cells show a higher energy metabolism compared to undifferentiated mesenchymal cells, indicating that UCP-1 have a significant role in adipogenic differentiation [ ].

In addition, UCP2 can be stimulated by PGC-1α with mitochondrial biogenesis and respiration, suggesting that PGC-1α is an upstream kinase that regulates UCP2 [ ]. In summary, UCP can convert the proton gradient which is produced by mitochondrial respiratory chain into thermic energy and closely related to adipogenic differentiation of MSCs.

SIRT3 and PGC-1α can induce SOD2, which regulate the ROS level and promote OXPHOS in the MSCs. In addition, PGC-1α can stimulate mitochondrial biogenesis and respiration through induction of UCP2, which can increase thermogenesis upon activation. Mechanismly, SIRT1 induces phosphorylation of LKB1 by deacetylation of LKB1.

LKB1 activates AMPK through phosphorylation of AMPK, and mTORC1 is a downstream target of AMPK, which is negatively regulated by AMPK and can phosphorylate PGC-1α.

And also SIRT1 can directly deacetylate the phosphorylated PGC-1α. Therefore, LKB1, AMPK, and SIRT1 all participate in the regulation of PGC-1α Fig. The signalling pathway and key factors which regulated the mitochondrial energy metabolism in MSCs. SIRT3 and PGC-1α can induce SOD2, which regulate the ROS levels and promote OXPHOS in MSCs.

LKB1 activates AMPK through phosphorylation of AMPK. And mTORC1 is a downstream target of AMPK, which is negatively regulated by AMPK, can phosphorylate PGC-1α. Therefore, LKB1, AMPK, and SIRT1 all participate in the regulation of PGC-1α.

HIF-1α, Hypoxia-inducible factor-1α. LKB1, Liver kinase B1. mTORC1, Mammalian target of rapamycin complex 1. ROS, Reactive oxygen species. SIRT, Sirtuin. SOD2, Superoxide dismutase 2. UCP, uncoupling protein. Mitochondria are crucial organelles responsible for the energy metabolism in cells.

They can affect several MSC functions such as their differentiation, ageing, immune regulation, apoptosis, proliferation, migration, and chemotaxis. Many studies have reported that mitochondrial morphology, distribution, transfer, biogenesis, dynamics, mitophagy, membrane potential, and ROS production play an important role in maintaining the functions of MSCs in local injury tissues.

Further studies have shown that the function of MSCs can be regulated by key effect factors of mitochondrial energy metabolism, such as HIF-1α, PGC-1α, sirtuin, SOD2, AMPK, and UCP.

In addition, mitochondrial biogenesis and mitochondrial energy metabolism are closely related to the differentiation process of MSCs. Meanwhile, the united signalling pathway analysis indicates that PGC-1α, which regulates mitochondrial biogenesis, is regulated by SIRT1, mTORC1, and AMPK, but also the upstream component of UCP2, suggesting that PGC-1α is a key factor affecting mitochondrial function.

Therefore, how to regulate the level of PGC-1α and then regulate the function of mitochondria can be further explored. Moreover, with the ageing problem becoming more and more serious, how to control the biogenesis, dynamics, mitophagy, and membrane potential of mitochondria to eliminate the damage of mitochondria, prevent MSCs from ageing, and promote tissue remodelling, so as to prevent the ageing of the organism, is also one of the questions that need to be explored.

In conclusion, the fate of MSCs can be affected by the change of the energy metabolism and can also be decided by the key factors which regulated the mitochondrial energy metabolism in MSCs.

Therefore, how to control the mitochondrial energy metabolism for regulating the proliferation, differentiation, and other functions of MSCs need to be further explored.

Nevertheless, techniques such as mitochondrial transplantation are less operable, mitochondria transfer by autologous MSCs are difficult, the mechanisms and signal targets of mitochondrial energy metabolism in MSCs are unclear, and the effects of modes of mitochondrial energy metabolism on the MSCs are indistinct; all these factors hinder the improvement in MSC functions and their applications in regenerative medicine.

Thus, regulating the mitochondrial function in MSCs, improving mitochondrial quality, and exploring mitochondria-related agents may be effective strategies to control and activate the functions of MSCs and employ them in regenerative medicine and treatment of ageing-related diseases.

So improving the operability of mitochondrial transplantation, achieving mitochondrial transfer mediated by autologous MSCs, and clarifying the mechanisms, signal targets, and modes of action of mitochondrial energy metabolism in MSCs need to be further performed.

These will provide the theoretical basis and candidate targets for promoting MSC function, tissue regeneration, and disease treatment based on mitochondrial function and energy metabolism regulation. Hu L, Liu Y, Wang S. Stem cell-based tooth and periodontal regeneration. Oral Dis. Article CAS PubMed Google Scholar.

Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. Article CAS PubMed PubMed Central Google Scholar. Chen L, Qu J, Cheng T, Chen X, Xiang C. Menstrual blood-derived stem cells: toward therapeutic mechanisms, novel strategies, and future perspectives in the treatment of diseases.

Stem Cell Res Ther. Zheng C, Chen J, Liu S, Jin Y. Stem cell-based bone and dental regeneration: a view of microenvironmental modulation.

Int J Oral Sci. Article PubMed PubMed Central CAS Google Scholar. Wang L, Yang L, Tian L, et al. Cannabinoid receptor 1 mediates homing of bone marrow-derived mesenchymal stem cells triggered by chronic liver injury.