Plasma mitochondriql CSF markers mitochondgial oxidative Memory enhancement techniques are increased in Functjon disease and Coenzyme Q and mitochondrial function by antiparkinsonian medication. Pooling data from some of the trials showed an Coenzyme Q and mitochondrial function in serum coenzyme Funnction 10 Coensyme three studies but no effect functkon left ventricular ejection fraction two studies or exercise capacity two studies Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content. Coenzyme Q biosynthetic proteins assemble in a substrate-dependent manner into domains at ER—mitochondria contacts. Recent Pat Drug Deliv Formul Following intraperitoneal administration of CoQ 10 in rat, only small amount of the supplement reaches the kidney, muscle, and brain. Coenzyme Q 10 is fat-soluble and is best absorbed with fat in a meal.

Coenzyme Q and mitochondrial function -

Two graphs are shown for dosage comparison because CoQ 10 treatment dosages were reported in 2 different units. In humans, mutations have so far been reported in all the genes required for CoQ 10 biosynthesis, except COQ3.

COQ3 is an O-methyltransferase and it is the only COQ protein that is required for more than one step in the CoQ biosynthetic pathway [ 46 ].

Thus, one possible explanation for the lack of reports of COQ3 patients is that, because it is required for two enzymatic steps, pathogenic mutations in COQ3 are more detrimental to CoQ production and thus are more likely to be lethal.

Among the reported PCoQD patients, The reason for the higher COQ8A and COQ8B patient counts is most likely because genetic screening studies were performed for COQ8A and COQ8B on a relative larger scale.

Two studies reported screening for COQ8A mutations in patients with ataxic symptoms, resulting in the identification of 69 patients carrying rare biallelic variants [ 15 , 39 ]. Screens for COQ8B mutations in patients with renal disorders, including nephrotic syndrome and chronic renal failure, were described in three studies, which in total reported the identification of 63 COQ8B patients [ 47 - 49 ].

COQ8A and COQ8B are orthologs of yeast Coq8p, which plays a regulatory role in CoQ biosynthesis [ 40 , 47 , 50 ]. COQ8A is expressed in most tissues, but there is a relative enrichment of COQ8B in podocytes [ 47 , 51 ]. Consistently, COQ8B patients were described to have a less severe clinical course and manifest largely kidney-limited phenotypes [ 47 , 52 ].

Thus, the mutation frequency observed for a given COQ gene is likely influenced by the role it plays in CoQ biosynthesis and its tissue expression pattern. Often CoQ 10 deficiency patients are started on oral CoQ 10 supplementation immediately after diagnosis. Various oral formulations of CoQ 10 are available [ 61 ].

The scientific literature as well as the general media mostly state that oral CoQ 10 supplementation is effective and thus that CoQ 10 deficiency is treatable [ 33 ]. However, to the best of our knowledge, there is no other evidence that could support such a belief than the set of studies reviewed here.

The final step of our analysis is based on published studies on 89 PCoQD patients for which we consider there to be sufficient information available to estimate the clinical effectiveness of the CoQ 10 treatment.

Of them, 65 cases fit our criteria for not-responding, including patients with age of onset ranging from neonatal to 42 years of age and that present with multi-system symptoms or primarily one organ-specific manifestation e. Among the 24 cases identified as responsive, 12 cases reported improvement of an ataxia rating score and 7 out of them are patients with COQ8A mutations for whom ataxia is often the most prominent symptom.

Five cases reported proteinuria improvement at a post-treatment follow-up, and in all five of them renal dysfunction was the only manifestation. However, many PCoQD patients with ataxia or kidney symptoms were reported to show no response or the condition continued to deteriorate after CoQ 10 treatment Table S4.

Therefore, the observed relative prevalence of positive effects on ataxia or proteinuria does not indicate that the kidneys and cerebellum are more sensitive to supplemental treatment with CoQ Furthermore, in patients with multisystem manifestations, effects were reported only for a few symptoms and most of the other symptoms still persisted after CoQ 10 treatment.

Detrimental effects of treatment interruption were noted in five cases, which potentially constitute the best evidence for some effectiveness of CoQ 10 therapy. However, as these are not blinded studies, the possibility of placebo effects remains of concern.

Overall, most descriptions of the effects of CoQ 10 treatment have incomplete information and lack a complete clinical picture. Doctors and patients are aware of the treatments i.

For these reasons, we consider the cases where a minimal effect only was reported as not responding to treatment. It has been hypothesized that CoQ treatment cannot reverse severe tissue damage due to PCoQD when the disease has already progressed too far before therapy is initiated [ 30 , 62 ].

However, animal studies with an unnatural CoQ biosynthetic precursor suggest that most phenotypes due to severe CoQ deficiency can be completely rescued by a partial replenishment of CoQ levels [ 63 - 65 ].

Therefore, it is reasonable to expect that significant clinical benefits should be possible even in severely impaired PCoQD patients if in fact a significant amount of CoQ 10 were absorbed and could reach affected tissues. The results from our analysis indicate that most PCoQD patients treated with CoQ 10 showed little or no response, and, in the cases of positive reports, the overall clinical benefit was only very limited.

This strongly suggests a lack of efficacy of CoQ 10 treatment. It is noteworthy that clinical trials have been conducted to assess the potential benefit of CoQ 10 in the treatment of patients with secondary CoQ 10 deficiency or mitochondrial disease.

CoQ 10 supplementation was shown to elicit no benefit to the patients with statin-induced myalgia [ 66 ]. To date, only few double-blind and randomized clinical trials evaluating CoQ 10 in the treatment of mitochondrial disorders have been completed.

There were reports of minor effects for improved muscle strength and attenuation of lactate rise post-exercise. However, the overall conclusion remained that CoQ 10 is ineffective for the treatment of patients with mitochondrial disorder, or at least there is no solid evidence to suggest otherwise [ 67 , 68 ].

CoQ 10 is extremely lipophilic and practically insoluble in water; therefore, to develop pharmaceutical CoQ preparations, a number of formulation strategies for insoluble compounds have been tried, such as oil solution, emulsion, cyclodextrin complexation, and liposomal nanoencapsulation [ 69 ] Presently, all currently marketed formulations of CoQ 10 are for oral administration only.

Like all dietary lipids, orally administered CoQ 10 is absorbed in the enterocytes, packaged into chylomicrons large lipoprotein particles and then transported via the lymphatics to the circulation Fig.

Increases several-fold above normal plasma level has been reported after CoQ 10 treatment [ 70 - 72 ]. However, it is not known how blood CoQ 10 concentration is related to effectiveness in relieving symptoms.

Moreover, the mechanism of tissue uptake of CoQ 10 is still poorly understood. In rodents, after oral CoQ 10 supplementation high concentrations of CoQ 10 were reported for several tissues including the liver, ovaries, brown adipocytes, and spleen after feeding CoQ 10 -supplemented food or water, but not for the heart, kidney, muscle and brain, the main affected tissues in PCoQD [ 63 , 73 - 77 ].

Key factors that influence the tissue or cellular uptake of CoQ 10 await future studies. There have been discussions on the possible merits of using the reduced form of CoQ 10 , also known as ubiquinol, to enhance the bioavailability of CoQ 10 [ 78 ]. Out of the 89 cases included in our final analysis, 6 were reported to be treated with ubiquinol Table S4 and S5.

Two met our criteria of responding and 4 did not. Thus, this data also does not point to better bioavailability of ubiquinol over regular CoQ 10 in PCoQD patients.

In sum, the results of the present review suggest the need to develop alternative strategies of providing CoQ 10 and stresses the need for caution when seeking to justify the widespread use of CoQ 10 for disease treatment or as a dietary supplement.

Our recent study suggests the possibility of intravenously administering CoQ 10 solubilized with the fungicide caspofungin to achieve much higher plasma concentration and thus more effective CoQ 10 therapy [ 79 ].

Furthermore, modified precursors of the quinone ring of CoQ 10 , for example, DHB, have been considered as potential alternative treatment option for some types of PCoQD [, 80, 81].

Future work is warranted to further explore these possibilities and unleash the full potential of CoQ 10 therapy. SH and YW designed the study. YW did literature searches and extracted data. SH verified data accuracy, narrative summaries, and interpretations.

Both authors contributed to the selection of included studies, evaluation of data quality, and data analyses. SH and YW wrote the manuscript together and approved the final manuscript. Research in the laboratory of SH is funded by a Foundation grant from the Canadian Institutes of Health Research: FDN SH is Campbell Chair of Developmental Biology.

SH and YW have received royalty payment from Clarus Therapeutics Holdings. SH also consults for Clarus Therapeutics Holdings. Table S1: Primary CoQ 10 deficiency patients identified by literature search. Table S3: Partial effects reported for CoQ 10 treatment of primary CoQ deficiency patients.

Table S5: Cases with positive outcomes following CoQ 10 treatment, classified as responding. View the discussion thread. Supplementary Material. Skip to main content. The efficacy of coenzyme Q 10 treatment in alleviating the symptoms of primary coenzyme Q 10 deficiency: a systematic review Ying Wang , Siegfried Hekimi.

Ying Wang. Abstract Coenzyme Q 10 CoQ 10 is necessary for mitochondrial electron transport. Studies of the effects of supplementation necessarily lacked controls and blinding. All reported positive responses to treatment only partially improved few symptoms. CoQ 10 supplementation for the treatment of any disease should be questioned.

Introduction Coenzyme Q 10 CoQ 10 , also known as ubiquinone UQ 10 , is composed of a redox active aromatic ring and a ten-repeat long polyprenyl sidechain. Figure 1. CoQ 10 in the mitochondria, pathology of CoQ 10 deficiency and oral supplementation.

MATERIALS AND METHODS Search strategy and selection criteria A literature search was performed in PubMed for studies that described PCoQD patients, up until May 01, Figure 2.

Flow diagram for identification and selection of primary CoQ 10 deficiency patients. Data analysis We synthesized data using tabulations that include narrative summaries. RESULTS The literature search yielded 78 published studies, from which a total of patients with PCoQD were identified.

View this table: View inline View popup Download powerpoint. Table 1. Primary CoQ 10 deficiency patients reported in the literature. Table 2. Reported partial effects of CoQ 10 treatment in primary CoQ deficiency patients. Table 3. Therapeutic efficacy of CoQ 10 suggested by the effects of treatment interruptions.

Figure 3. The violin plots of CoQ 10 treatment dose and duration. Data Availability All data produced in the present work are contained in the manuscript.

FUNDING Research in the laboratory of SH is funded by a Foundation grant from the Canadian Institutes of Health Research: FDN Table S2: Cases excluded from the final analysis and reasons for their exclusion.

Table S4: Patient cases classified as not responding to CoQ 10 treatment. S1: The violin plot of total CoQ 10 amounts taken. REFERENCE 1.

and S. Hekimi , Understanding Ubiquinone. Trends Cell Biol , OpenUrl CrossRef PubMed. Quinzii , C. Front Physiol , Lenaz , G. and M. Genova , Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject.

OpenUrl CrossRef PubMed Web of Science. Crane , F. J Am Coll Nutr , Morre , D. and D. Morre , Non-mitochondrial coenzyme Q. Biofactors , Bentinger , M. Brismar , and G. Dallner , The antioxidant role of coenzyme Q.

Mitochondrion , S41 — Tran , U. and C. Clarke , Endogenous synthesis of coenzyme Q in eukaryotes. S62 — Wang , Y. Hekimi , Molecular genetics of ubiquinone biosynthesis in animals.

Crit Rev Biochem Mol Biol , Stefely , J. Pagliarini , Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. Trends Biochem Sci , Hekimi , The Complexity of Making Ubiquinone. Trends Endocrinol Metab , Tsui , H. Clarke , Ubiquinone Biosynthetic Complexes in Prokaryotes and Eukaryotes.

Cell Chem Biol , Ogasahara , S. Proc Natl Acad Sci U S A , Hughes , B. Harrison , and S. Hekimi , Estimating the occurrence of primary ubiquinone deficiency by analysis of large-scale sequencing data. Sci Rep , Doimo , M. Mol Syndromol , OpenUrl PubMed. Traschutz , A. This product is not intended to diagnose, treat, cure, or prevent any disease.

MitoQ supplement testimonials may not be typical and individual results may vary. Feb 7, AT A GLANCE — CoQ10 is a critical antioxidant for safeguarding and supporting mitochondria, which are essential for energy production in cells. Although we can take coQ10 supplements, next to none of it gets inside our mitochondria where it is needed most.

WRITTEN BY MitoQ PUBLISHED Feb 7, Shop now. William Stow BSc Hons , MitoQ Chief Scientific Officer. GENERAL RESEARCH. An advanced form of CoQ10, clinically proven to get deep within the mitochondria.

New Jersey, United States: John Wiley and Sons; Geng AL, Guo YM, Yuan J. Effects of dietary L-carnitine and coenzyme Q10 supplementation on performance and ascites mortality of broilers.

Archives of Animal Nutrition. Kaikkonen J, Nyyssonen K, Porkkala-Sarataho E, Poulsen HE, Metsa-Ketela T. Free Radical Biological Medicine. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function.

Biochimica et Biophysica Acta: Molecular Basis of Disease. Krizman PJ, Prosek M, Smidovnik A, Wondra AG, Glaser R, Zelenko B, et al. Poultry products with increased content of CoQ10 prepared from chickens fed with supplemental CoQ In: Eissa AHA, editor.

Trends in Vital Food and Control Engineering. Rijeka, Croatia. ISBN IntechOpen; Ramasarma T. A touch of history and a peep into the future of the lipidquinone known as coenzyme Q and ubiquinone. Current Science. Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM. Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders.

Molecular Genetics and Metabolism. Fato R, Bertoli E, Castelli GP, Lenaz G. Fluidizing effect of endogenous ubiquinone in bovine heart mitochondrial membranes.

Takayanagi R, Takeshige K, Minakami S. NADH and NADPH dependent lipid peroxidation in bovine heart submitochondrial particles. Dependence on the rate of electron flow in the respiratory chain and an antioxidant role of ubiquinol.

Journal of Biochemistry. Redfearn ER. Mode of action of ubiquinones coenzymes Q in electron transport systems. Vitamins Hormones. Battino M, Fato R, Parenti-Castelli G, Lenaz G. Coenzyme Q can control the efficiency of oxidative phosphorylation.

International Journal of Tissue Reactions. Bhagavan HN, Chopra RK. Coenzyme Q Absorption, tissue uptake, metabolism and pharmacokinetics. Free Radical Research. Wang Y, Oxer D, Hekimi S. Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis.

Nature Communications. DOI: Amselem S. Solid lipid compositions of lipophilic compounds for enhanced oral bioavailability.

Patent No. htm Fir MM, Milivojevic L, Prosek M, Smidovnik A. Property studies of coenzyme Qcyclodextrins complexes. Acta Chimica Slovenica. Natural Medicines Comprehensive Database: Coenzymes Q10 Monograph. com Elmberger PG, Kalen A, Appelkvist EL, Dallner G.

In vitro and in vivo synthesis of dolichol and other main mevalonate products in various organs of the rat. European Journal of Biochemistry. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q.

Biochimica et Biophysica Acta BBA -Biomembranes. Studies on ubiquinone. Journal of Scientific and Industrial Research; 27 Zlatohlavek L, Vrablik B, Grauova EM, Ceska R. The effect of coenzyme Q10 in statin myopathy. Neuroendocrinology Letters. Ioana VS, Lasio V, Uivarosan D.

Stimulation of biosynthesis of coenzyme Q10 by Sacharomyces cerevisiae under the influence of vitamin B1. Analele Universitatii Din Oradea.

Lambrechts P, Siebrecht S. Coenzyme Q10 and ubiquinol as adjunctive therapy for heart failure. Agro Food Industry Hi Tech. Tafazoli A. Coenzyme Q10 in breast cancer care. Future Oncology.

Hill GJ, Shriver BJ, Arnett DB. Examining intentions to use CoQ10 amongst breast cancer patients. American Journal of Health Behavior. Complementary treatments highlighted at recent meeting. Oncology Williston Park, N.

Cardiotoxicity of conservative treatment of solid tumors. Portakal O, Ozkaya O, Erden Inal M, Bozan B, Kosan M, Sayek I. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients.

Clinical Biochemistry. Sinatra ST. Care, cancer and coenzyme Q Journal of the American College of Cardiology. Low plasma coenzyme Q 10 levels and breast cancer risk in Chinese women.

Bahar M, Khaghani S, Pasalar P. Exogenous coenzyme Q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model. Nutrition Journal. Greenlee H, Shaw J, Lau YK, Naini A, Maurer M. Lack of effect of coenzyme q10 on doxorubicin cytotoxicity in breast cancer cell cultures.

Integrative Cancer Therapies. Perumal SS, Shanthi P, Sachdanandam P. Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin and CoQ Effects on lipid peroxidation and antioxidants in mitochondria.

Chemico-biological Interactions. Lockwood K, Moesgaard S, Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q Biochemical and Biophysical Research Communications.

Lockwood K, Moesgaard S, Hanioka T, Folkers K. Molecular Aspects of Medicine. Lockwood K, Moesgaard S, Yamamoto T, Folkers K. Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases.

Bjorklund G. The adjuvant nutritional intervention in cancer ANICA trial. Nutrition and Cancer. Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA levels in breast cancer patients undergoing tamoxifen therapy.

Biological and Pharmaceutical Bulletin. Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy.

The British Journal of Nutrition. Premkumar VG, Yuvaraj S, Sathish S, Shanthi P, Sachdanandam P. Anti-angiogenic potential of Coenzyme Q10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy.

Vascular Pharmacology. Serum cytokine levels of interleukin-1beta, -6, -8, tumour necrosis factor-alpha and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with co-enzyme Q 10 , riboflavin and niacin.

Basic and Clinical Pharmacology and Toxicology. Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Augmented antioxidant status in tamoxifen treated postmenopausal women with breast cancer on coadministration with coenzyme Q10, niacin and riboflavin. Cancer Chemotherapy and Pharmacology.

Yuvaraj S, Premkumar VG, Shanthi P, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Effect of coenzyme Q 10 , riboflavin and niacin on tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles.

Breast Cancer Research and Treatment. Ameliorating effect of coenzyme Q10, riboflavin and niacin in tamoxifen-treated postmenopausal breast cancer patients with special reference to lipids and lipoproteins. Iwase S, Kawaguchi T, Yotsumoto D. Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: A multi-institutional, randomized, exploratory trial JORTC-CAM Supportive Care in Cancer.

Lesser GJ, Case D, Stark N.

Coenzyme Q 10 fknction a member of the ubiquinone Coenzyme Q and mitochondrial function of compounds. All animals, Codnzyme humans, can synthesize funnction, hence, coenzyme Q 10 is not considered a mitohcondrial Coenzyme Q and mitochondrial function. Anr name ubiquinone Balanced diet advice to the ubiquitous presence of these compounds in living organisms and their chemical structure, which contains a functional group known as a benzoquinone. Ubiquinones are fat-soluble molecules with anywhere from 1 to 12 isoprene 5-carbon units. The ubiquinone found in humans, ubidecaquinone or coenzyme Q 10has a "tail" of 10 isoprene units a total of 50 carbon atoms attached to its benzoquinone "head" Figure 1 1. We Bioavailability of phytochemicals accumulated evidence that coenzyme Q CoQ concentration in the Coenzyme Q and mitochondrial function functjon is not funcrion for NADH oxidation Natural vitamin resources is saturating for succinate and glycerolphosphate oxidation. As a result of its kinetic properties CoQ Amazon Office Supplies changes must yield changes in respiration rates. This provides a rationale for the reported Coenzyme Q and mitochondrial function mitochonrrial of CoQ Coenzme conditions Coenzym its concentration is decreased, as has been reported in tissues from aged rats; we have failed, however, to detect any specific CoQ decrease in mitochondria from several tissues of aged rats. We can, however, predict from the kinetic bases that CoQ would ameliorate respiration rate also under conditions in which a defect is present in regions not involving the quinone. CoQ incorporation in perfused liver is attempted in order to find experimental systems for investigating its protecting effect. Liposomal CoQ 10 perfused in rat livers where CoQ 9 is the main homolog is incorporated mainly in lysosomes, and its increase in the crude mitochondrial fraction could be mainly ascribed to residual lysosomal contamination.

Coenzyme Q and mitochondrial function -

Moreover, CoQ 10 is recommended for treating a wide range of other conditions e. By estimation, the global market size of CoQ 10 amounts to close to M USD a year.

This review aims to summarize and evaluate the available evidence for the effectiveness of CoQ 10 supplementation for the treatment of PCoQD.

Patients with PCoQD should be the most amenable to CoQ 10 treatment because their CoQ 10 deficiency is the only cause of all their symptoms and therefore CoQ 10 treatment is simple replacement therapy. Thus, examining outcomes of CoQ 10 treatment for these patients is the first key step to address the effectiveness of any CoQ 10 therapy and to promote a rational use of CoQ 10 for disease treatment or as a health supplement.

A literature search was performed in PubMed for studies that described PCoQD patients, up until May 01, The PubMed query used is given in Supporting Information. The references cited in the articles identified were manually screened for any additional relevant study.

We imposed no publication status or language restrictions. We considered any type of study regardless of research design. The following information was sought in each paper: descriptive characteristics of PCoQD patients including sex, age of onset, major symptoms, age at the last reported exam or death, molecular lesions in COQ genes or proteins, severity of CoQ 10 deficit, respiratory chain complex RCC activities, CoQ 10 treatment received and clinical outcomes, and laboratory tests known to be relevant to mitochondrial disease.

CoQ 10 levels and RCC activities are most often reported in patient-derived skin fibroblasts or muscle biopsies. Study data were extracted by one reviewer YW and verified by another reviewer SH for accuracy, narrative summaries, and interpretation.

When data were reported more than once for the same patients, which was exceedingly rare, the data that were included were those from the most recent comprehensive report. If no data on patient treatment with CoQ 10 was provided in a study, or if patients were treated but outcome data was not reported, or the reported effects were contradictory or ambiguous, the study was excluded from the final data synthesis Fig.

We synthesized data using tabulations that include narrative summaries. Fulfilling any one of the first two criteria is defined as responding with an objective description of the response.

Whereas if symptom improvement was described without relying on any quantifiable measure, we categorize it as a subjective description of the response to CoQ 10 therapy. No restriction on CoQ 10 dosage dose, formulation, dose frequency , time of initial treatment, duration of treatment, or concurrent treatments was made.

The two authors independently assigned the patient cases to the categories. Disagreements were resolved by discussion and consensus. The literature search yielded 78 published studies, from which a total of patients with PCoQD were identified.

Their characteristics are summarized in Table 1 , and details are available in Table S1. Of the PCoQD patients, [ Following the exclusion criteria, 53 treated patients were removed from the final analysis Table S2.

Among the excluded patients, 16 were excluded because the reported follow-up findings were judged to be ambiguous or inadequate to judge treatment efficiency, for example reports that mention symptom stabilization or CoQ 10 treatment combined with other simultaneous treatments.

All other exclusions were because no treatment outcome was reported. In the final analysis, we included and assessed a total of 89 patients. The results are shown in Table 2. Details, including total count of patients treated and numbers of exclusions for each gene, can be found in Table S3.

We classified 65 out of the 89 patients Among those, there are nine cases in which patients showed infantile onset and multisystem involvement. Such cases may be more challenging to treat, but this is only speculation.

Of the 24 cases Note, however, that all responses were partial, and responses are frequently only observed with a single symptom.

Four out of the five also reported recovery to some extent following treatment resumption. These cases potentially provide the most tantalizing evidence for a partial efficacy of CoQ 10 treatment for CoQ deficiency.

We should note, however, that the possibility of placebo effects cannot be excluded. Of the other 15 cases of responses with objective description, four cases reported a decrease of proteinuria after CoQ 10 treatment as an indication of kidney function improvement and ten reported a reduction in a severity score of ataxia or another motor performance test at a follow-up.

However, five of the patients classified as responders because of an amelioration of proteinuria had only kidney symptoms, and in two cases only proteinuria. Treatment effects established by quantitative or semi-quantitative measures to describe the response to CoQ 10 treatment were counted as responding with objective description, while descriptions of positive effects but without relying on a quantitative or semi-quantitative measures were counted as responding with subjective description.

As shown in Fig. No substantial adverse effects have been reported for the CoQ 10 -treated PCoQD patients. However, an adverse reaction has been reported in one case of treatment with the synthetic CoQ analogue idebenone which has a hydroxydecyl instead of a decaprenyl side chain and higher solubility than CoQ 10 [ 45 ].

Two graphs are shown for dosage comparison because CoQ 10 treatment dosages were reported in 2 different units. In humans, mutations have so far been reported in all the genes required for CoQ 10 biosynthesis, except COQ3. COQ3 is an O-methyltransferase and it is the only COQ protein that is required for more than one step in the CoQ biosynthetic pathway [ 46 ].

Thus, one possible explanation for the lack of reports of COQ3 patients is that, because it is required for two enzymatic steps, pathogenic mutations in COQ3 are more detrimental to CoQ production and thus are more likely to be lethal. Among the reported PCoQD patients, The reason for the higher COQ8A and COQ8B patient counts is most likely because genetic screening studies were performed for COQ8A and COQ8B on a relative larger scale.

Two studies reported screening for COQ8A mutations in patients with ataxic symptoms, resulting in the identification of 69 patients carrying rare biallelic variants [ 15 , 39 ]. Screens for COQ8B mutations in patients with renal disorders, including nephrotic syndrome and chronic renal failure, were described in three studies, which in total reported the identification of 63 COQ8B patients [ 47 - 49 ].

COQ8A and COQ8B are orthologs of yeast Coq8p, which plays a regulatory role in CoQ biosynthesis [ 40 , 47 , 50 ].

COQ8A is expressed in most tissues, but there is a relative enrichment of COQ8B in podocytes [ 47 , 51 ]. Consistently, COQ8B patients were described to have a less severe clinical course and manifest largely kidney-limited phenotypes [ 47 , 52 ].

Thus, the mutation frequency observed for a given COQ gene is likely influenced by the role it plays in CoQ biosynthesis and its tissue expression pattern.

Often CoQ 10 deficiency patients are started on oral CoQ 10 supplementation immediately after diagnosis. Various oral formulations of CoQ 10 are available [ 61 ]. The scientific literature as well as the general media mostly state that oral CoQ 10 supplementation is effective and thus that CoQ 10 deficiency is treatable [ 33 ].

However, to the best of our knowledge, there is no other evidence that could support such a belief than the set of studies reviewed here. The final step of our analysis is based on published studies on 89 PCoQD patients for which we consider there to be sufficient information available to estimate the clinical effectiveness of the CoQ 10 treatment.

Of them, 65 cases fit our criteria for not-responding, including patients with age of onset ranging from neonatal to 42 years of age and that present with multi-system symptoms or primarily one organ-specific manifestation e. Among the 24 cases identified as responsive, 12 cases reported improvement of an ataxia rating score and 7 out of them are patients with COQ8A mutations for whom ataxia is often the most prominent symptom.

Five cases reported proteinuria improvement at a post-treatment follow-up, and in all five of them renal dysfunction was the only manifestation. However, many PCoQD patients with ataxia or kidney symptoms were reported to show no response or the condition continued to deteriorate after CoQ 10 treatment Table S4.

Therefore, the observed relative prevalence of positive effects on ataxia or proteinuria does not indicate that the kidneys and cerebellum are more sensitive to supplemental treatment with CoQ Furthermore, in patients with multisystem manifestations, effects were reported only for a few symptoms and most of the other symptoms still persisted after CoQ 10 treatment.

Detrimental effects of treatment interruption were noted in five cases, which potentially constitute the best evidence for some effectiveness of CoQ 10 therapy.

However, as these are not blinded studies, the possibility of placebo effects remains of concern. Overall, most descriptions of the effects of CoQ 10 treatment have incomplete information and lack a complete clinical picture.

Doctors and patients are aware of the treatments i. For these reasons, we consider the cases where a minimal effect only was reported as not responding to treatment. It has been hypothesized that CoQ treatment cannot reverse severe tissue damage due to PCoQD when the disease has already progressed too far before therapy is initiated [ 30 , 62 ].

However, animal studies with an unnatural CoQ biosynthetic precursor suggest that most phenotypes due to severe CoQ deficiency can be completely rescued by a partial replenishment of CoQ levels [ 63 - 65 ]. Therefore, it is reasonable to expect that significant clinical benefits should be possible even in severely impaired PCoQD patients if in fact a significant amount of CoQ 10 were absorbed and could reach affected tissues.

The results from our analysis indicate that most PCoQD patients treated with CoQ 10 showed little or no response, and, in the cases of positive reports, the overall clinical benefit was only very limited. This strongly suggests a lack of efficacy of CoQ 10 treatment. It is noteworthy that clinical trials have been conducted to assess the potential benefit of CoQ 10 in the treatment of patients with secondary CoQ 10 deficiency or mitochondrial disease.

CoQ 10 supplementation was shown to elicit no benefit to the patients with statin-induced myalgia [ 66 ]. To date, only few double-blind and randomized clinical trials evaluating CoQ 10 in the treatment of mitochondrial disorders have been completed. There were reports of minor effects for improved muscle strength and attenuation of lactate rise post-exercise.

However, the overall conclusion remained that CoQ 10 is ineffective for the treatment of patients with mitochondrial disorder, or at least there is no solid evidence to suggest otherwise [ 67 , 68 ]. CoQ 10 is extremely lipophilic and practically insoluble in water; therefore, to develop pharmaceutical CoQ preparations, a number of formulation strategies for insoluble compounds have been tried, such as oil solution, emulsion, cyclodextrin complexation, and liposomal nanoencapsulation [ 69 ] Presently, all currently marketed formulations of CoQ 10 are for oral administration only.

Like all dietary lipids, orally administered CoQ 10 is absorbed in the enterocytes, packaged into chylomicrons large lipoprotein particles and then transported via the lymphatics to the circulation Fig.

Increases several-fold above normal plasma level has been reported after CoQ 10 treatment [ 70 - 72 ]. However, it is not known how blood CoQ 10 concentration is related to effectiveness in relieving symptoms. Moreover, the mechanism of tissue uptake of CoQ 10 is still poorly understood.

In rodents, after oral CoQ 10 supplementation high concentrations of CoQ 10 were reported for several tissues including the liver, ovaries, brown adipocytes, and spleen after feeding CoQ 10 -supplemented food or water, but not for the heart, kidney, muscle and brain, the main affected tissues in PCoQD [ 63 , 73 - 77 ].

Key factors that influence the tissue or cellular uptake of CoQ 10 await future studies. There have been discussions on the possible merits of using the reduced form of CoQ 10 , also known as ubiquinol, to enhance the bioavailability of CoQ 10 [ 78 ]. Out of the 89 cases included in our final analysis, 6 were reported to be treated with ubiquinol Table S4 and S5.

Two met our criteria of responding and 4 did not. Thus, this data also does not point to better bioavailability of ubiquinol over regular CoQ 10 in PCoQD patients.

In sum, the results of the present review suggest the need to develop alternative strategies of providing CoQ 10 and stresses the need for caution when seeking to justify the widespread use of CoQ 10 for disease treatment or as a dietary supplement.

Our recent study suggests the possibility of intravenously administering CoQ 10 solubilized with the fungicide caspofungin to achieve much higher plasma concentration and thus more effective CoQ 10 therapy [ 79 ]. Furthermore, modified precursors of the quinone ring of CoQ 10 , for example, DHB, have been considered as potential alternative treatment option for some types of PCoQD [, 80, 81].

Future work is warranted to further explore these possibilities and unleash the full potential of CoQ 10 therapy. SH and YW designed the study. YW did literature searches and extracted data.

SH verified data accuracy, narrative summaries, and interpretations. Both authors contributed to the selection of included studies, evaluation of data quality, and data analyses.

SH and YW wrote the manuscript together and approved the final manuscript. Research in the laboratory of SH is funded by a Foundation grant from the Canadian Institutes of Health Research: FDN SH is Campbell Chair of Developmental Biology.

SH and YW have received royalty payment from Clarus Therapeutics Holdings. SH also consults for Clarus Therapeutics Holdings. Table S1: Primary CoQ 10 deficiency patients identified by literature search. Table S3: Partial effects reported for CoQ 10 treatment of primary CoQ deficiency patients.

Table S5: Cases with positive outcomes following CoQ 10 treatment, classified as responding. View the discussion thread. Supplementary Material. Skip to main content.

The efficacy of coenzyme Q 10 treatment in alleviating the symptoms of primary coenzyme Q 10 deficiency: a systematic review Ying Wang , Siegfried Hekimi. Ying Wang. Abstract Coenzyme Q 10 CoQ 10 is necessary for mitochondrial electron transport.

Studies of the effects of supplementation necessarily lacked controls and blinding. All reported positive responses to treatment only partially improved few symptoms. CoQ 10 supplementation for the treatment of any disease should be questioned.

Introduction Coenzyme Q 10 CoQ 10 , also known as ubiquinone UQ 10 , is composed of a redox active aromatic ring and a ten-repeat long polyprenyl sidechain. Figure 1. CoQ 10 in the mitochondria, pathology of CoQ 10 deficiency and oral supplementation.

MATERIALS AND METHODS Search strategy and selection criteria A literature search was performed in PubMed for studies that described PCoQD patients, up until May 01, Figure 2. Flow diagram for identification and selection of primary CoQ 10 deficiency patients.

Data analysis We synthesized data using tabulations that include narrative summaries. RESULTS The literature search yielded 78 published studies, from which a total of patients with PCoQD were identified.

View this table: View inline View popup Download powerpoint. Table 1. Primary CoQ 10 deficiency patients reported in the literature. Table 2.

Reported partial effects of CoQ 10 treatment in primary CoQ deficiency patients. Table 3. Therapeutic efficacy of CoQ 10 suggested by the effects of treatment interruptions.

Figure 3. The violin plots of CoQ 10 treatment dose and duration. Data Availability All data produced in the present work are contained in the manuscript. FUNDING Research in the laboratory of SH is funded by a Foundation grant from the Canadian Institutes of Health Research: FDN Table S2: Cases excluded from the final analysis and reasons for their exclusion.

Table S4: Patient cases classified as not responding to CoQ 10 treatment. S1: The violin plot of total CoQ 10 amounts taken. REFERENCE 1. and S. Hekimi , Understanding Ubiquinone. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats.

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Wilcock, D. Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. Neuroinflammation Superoxide dismutase SOD activity was increased in accordance with CoQ10 supplementation in broilers and in rats [ 74 ]. An increase in hepatic SOD and anti-ROS capacity in broilers was observed by CoQ10 supplementation [ 55 ].

The supplementation of CoQ10 increases the SOD activity by antagonizing nitric oxide NO inactivation, thereby making more NO availability for the biological function that leads to extracellular SOD gene expression.

This synergistic action of CoQ10 is possible as it acts as a primary regenerating antioxidant [ 75 ]. However, supplementation at 40 mg kgG1 of diet resulted in no effect on serum vitamin E and SOD levels.

This ineffectiveness of CoQ10 at 40 mg kgG1 of diet is due to the auto-oxidation of CoQ10 resulting in higher production of mitochondrial reactive oxygen species ROS , which leads to oxidative stress in the body.

The development of auto-oxidation was observed in birds fed higher level of CoQ10 for prolonged duration. The content of CoQ10 in different body tissues is well studied in human subjects, but there are not enough studies in farm animals or birds. The highest concentration of CoQ10 was found in the most active organs like heart, kidney and liver.

The CoQ10 concentration depends on a balance between inputs and outputs. Inputs are the level of CoQ10, which is endogenously synthesized, plus dietary supply and the outputs are the usage by oxidative stress and cellular metabolism. An adult human body has approximately 2 g of CoQ10, where a daily replacement of 0.

Therefore, an average body CoQ10 content turnover rate was around 4 days and dietary supply becomes essential with impairment in endogenous synthesis.

The body content of CoQ10 decreased rapidly after the age of 40 years in humans with reduced biosynthesis. CoQ10 supplementation reversed the reduced circulating CoQ10 concentrations in statin-treated subjects as statin inhibits the pathways involved in both cholesterol and CoQ10 supplementation.

Various authors recommended daily intake of CoQ10 of about 30— mg for healthy people over 40 years and 60— mg for those undergoing an adjunctive therapy for some medical conditions. The CoQ10 level in human tissues varies with inappropriate nutrition, smoking and different medical conditions such as cardiomyopathy, diabetes and neurological disorder conditions [ 76 ].

Similarly in broiler chicken, the concentration of CoQ10 among different body tissues was recorded Table 1 [ 77 ]. Concentration of CoQ10 in various body tissues [ 77 ].

Among the organelles, larger amount of CoQ10 is found in mitochondria of heart cells Being lipophilic, vegetable oils especially rape seed and peanut oils have a high content This again proved that CoQ10 is required more by tissues that are very active.

CoQ10 to cholesterol index QCI is increasingly used as a measure for assessment of meat quality. QCI was used as a reliable indicator of oxidative status, and the possible oxidative stresses induced by different food ingredients and consider them as oxidant foods [ 8 ].

In simple terms, muscles with higher oxidative stress due to either metabolic activity or food would have a reduction of QCI value. Due to its antioxidant property, CoQ10 supplementation will be helpful in reducing drip loss during meat storage.

Supplementation with CoQ10 at 40 mg kgG1 diet improved breast muscle yield and reduced the drip loss in broilers [ 60 ]. The reduction in muscle drip loss was attributed to the reduced reactive oxygen metabolites, thereby improving the cell membrane integrity and improved water retention.

The role of coenzyme Q10 is widely being studied under various health conditions including cancer and cardiac hypertrophy. Its importance in normal healthy life is quite evident and physicians are prescribing it for oral intake for persons who continuously smoke as well as for those under statin drug therapy.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Open access peer-reviewed chapter Coenzyme Q Regulators of Mitochondria and beyond Written By Gopi Marappan.

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Choose citation style Select format Bibtex RIS Download citation. IntechOpen Apolipoproteins, Triglycerides and Cholesterol Edited by Viduranga Y. From the Edited Volume Apolipoproteins, Triglycerides and Cholesterol Edited by Viduranga Y.

Jovandaric Book Details Order Print. Chapter metrics overview Chapter Downloads View Full Metrics. Impact of this chapter. Abstract The role of coenzyme Q10 CoQ10 was relatively unknown except its involvement in the oxidative phosphorylation at electron transport chain. Keywords coenzyme Q10 antioxidant mitochondrial regulators reduced cholesterol synthesis cancer.

Introduction Coenzymes are the cofactors in the body, which are essential for numerous enzymatic reactions at various levels. Unlike vitamins K and E, exogenous CoQ is absorbed into liver and not in other tissues. Table 1. References 1. Crane FL, Hatefi Y, Lester RL, Widmer C. Isolation of a quinone from beef heart mitochondria.

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Studies on ubiquinone. Journal of Scientific and Industrial Research; 27 Zlatohlavek L, Vrablik B, Grauova EM, Ceska R. The effect of coenzyme Q10 in statin myopathy. Neuroendocrinology Letters.

Mitochlndrial you mitochondrlal visiting Coenzyme Q and mitochondrial function. You are Coenzyme Q and mitochondrial function a browser version functiin limited support for CSS. To obtain the best experience, we recommend you use mitoxhondrial more up to date browser or turn off compatibility mode in Funtcion Explorer. In Carb cycling for endurance athletes meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Coenzyme Q or ubiquinone is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis.

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Gerald Quigley: Mitochondria, CoQ10, and Ubiquinol