During the Krebs cycle, high-energy molecules, including ATP, NADH, and FADH2, are created. NADH and FADH2 then pass electrons through the electron transport chain in the mitochondria to generate more ATP molecules. Figure 4. During the Krebs cycle, each pyruvate that is generated by glycolysis is converted into a two-carbon acetyl CoA molecule.

The acetyl CoA is systematically processed through the cycle and produces high- energy NADH, FADH2, and ATP molecules. The three-carbon pyruvate molecule generated during glycolysis moves from the cytoplasm into the mitochondrial matrix, where it is converted by the enzyme pyruvate dehydrogenase into a two-carbon acetyl coenzyme A acetyl CoA molecule.

This reaction is an oxidative decarboxylation reaction. Acetyl CoA enters the Krebs cycle by combining with a four-carbon molecule, oxaloacetate, to form the six-carbon molecule citrate, or citric acid, at the same time releasing the coenzyme A molecule.

The six-carbon citrate molecule is systematically converted to a five-carbon molecule and then a four-carbon molecule, ending with oxaloacetate, the beginning of the cycle. Along the way, each citrate molecule will produce one ATP, one FADH2, and three NADH. The FADH2 and NADH will enter the oxidative phosphorylation system located in the inner mitochondrial membrane.

In addition, the Krebs cycle supplies the starting materials to process and break down proteins and fats. To start the Krebs cycle, citrate synthase combines acetyl CoA and oxaloacetate to form a six-carbon citrate molecule; CoA is subsequently released and can combine with another pyruvate molecule to begin the cycle again.

The aconitase enzyme converts citrate into isocitrate. In two successive steps of oxidative decarboxylation, two molecules of CO2 and two NADH molecules are produced when isocitrate dehydrogenase converts isocitrate into the five-carbon α-ketoglutarate, which is then catalyzed and converted into the four-carbon succinyl CoA by α-ketoglutarate dehydrogenase.

The enzyme succinyl CoA dehydrogenase then converts succinyl CoA into succinate and forms the high-energy molecule GTP, which transfers its energy to ADP to produce ATP. Succinate dehydrogenase then converts succinate into fumarate, forming a molecule of FADH2. Oxaloacetate is then ready to combine with the next acetyl CoA to start the Krebs cycle again see Figure 4.

For each turn of the cycle, three NADH, one ATP through GTP , and one FADH2 are created. Each carbon of pyruvate is converted into CO2, which is released as a byproduct of oxidative aerobic respiration.

The electron transport chain ETC uses the NADH and FADH 2 produced by the Krebs cycle to generate ATP. Electrons from NADH and FADH 2 are transferred through protein complexes embedded in the inner mitochondrial membrane by a series of enzymatic reactions.

In the presence of oxygen, energy is passed, stepwise, through the electron carriers to collect gradually the energy needed to attach a phosphate to ADP and produce ATP.

The role of molecular oxygen, O 2 , is as the terminal electron acceptor for the ETC. This means that once the electrons have passed through the entire ETC, they must be passed to another, separate molecule.

This is the basis for your need to breathe in oxygen. Without oxygen, electron flow through the ETC ceases.

Figure 5. The electrons released from NADH and FADH 2 are passed along the chain by each of the carriers, which are reduced when they receive the electron and oxidized when passing it on to the next carrier.

Each of these reactions releases a small amount. The accumulation of these protons in the space between the membranes creates a proton gradient with respect to the mitochondrial matrix. Also embedded in the inner mitochondrial membrane is an amazing protein pore complex called ATP synthase.

This rotation enables other portions of ATP synthase to encourage ADP and P i to create ATP. In accounting for the total number of ATP produced per glucose molecule through aerobic respiration, it is important to remember the following points:.

Therefore, for every glucose molecule that enters aerobic respiration, a net total of 36 ATPs are produced see Figure 6. Figure 6. Carbohydrate metabolism involves glycolysis, the Krebs cycle, and the electron transport chain. Gluconeogenesis is the synthesis of new glucose molecules from pyruvate, lactate, glycerol, or the amino acids alanine or glutamine.

This process takes place primarily in the liver during periods of low glucose, that is, under conditions of fasting, starvation, and low carbohydrate diets. So, the question can be raised as to why the body would create something it has just spent a fair amount of effort to break down?

Certain key organs, including the brain, can use only glucose as an energy source; therefore, it is essential that the body maintain a minimum blood glucose concentration. When the blood glucose concentration falls below that certain point, new glucose is synthesized by the liver to raise the blood concentration to normal.

Gluconeogenesis is not simply the reverse of glycolysis. There are some important differences Figure 7. Pyruvate is a common starting material for gluconeogenesis. First, the pyruvate is converted into oxaloacetate. Oxaloacetate then serves as a substrate for the enzyme phosphoenolpyruvate carboxykinase PEPCK , which transforms oxaloacetate into phosphoenolpyruvate PEP.

From this step, gluconeogenesis is nearly the reverse of glycolysis. PEP is converted back into 2-phosphoglycerate, which is converted into 3-phosphoglycerate.

Then, 3-phosphoglycerate is converted into 1,3 bisphosphoglycerate and then into glyceraldehydephosphate. Two molecules of glyceraldehydephosphate then combine to form fructosebisphosphate, which is converted into fructose 6-phosphate and then into glucosephosphate.

Finally, a series of reactions generates glucose itself. In gluconeogenesis as compared to glycolysis , the enzyme hexokinase is replaced by glucosephosphatase, and the enzyme phosphofructokinase-1 is replaced by fructose-1,6-bisphosphatase.

This helps the cell to regulate glycolysis and gluconeogenesis independently of each other. As will be discussed as part of lipolysis, fats can be broken down into glycerol, which can be phosphorylated to form dihydroxyacetone phosphate or DHAP.

DHAP can either enter the glycolytic pathway or be used by the liver as a substrate for gluconeogenesis. Figure 7. Gluconeogenesis is the synthesis of glucose from pyruvate, lactate, glycerol, alanine, or glutamate. Changes in body composition, including reduced lean muscle mass, are mostly responsible for this decrease.

The most dramatic loss of muscle mass, and consequential decline in metabolic rate, occurs between 50 and 70 years of age. Loss of muscle mass is the equivalent of reduced strength, which tends to inhibit seniors from engaging in sufficient physical activity.

This results in a positive-feedback system where the reduced physical activity leads to even more muscle loss, further reducing metabolism. There are several things that can be done to help prevent general declines in metabolism and to fight back against the cyclic nature of these declines.

These include eating breakfast, eating small meals frequently, consuming plenty of lean protein, drinking water to remain hydrated, exercising including strength training , and getting enough sleep. These measures can help keep energy levels from dropping and curb the urge for increased calorie consumption from excessive snacking.

While these strategies are not guaranteed to maintain metabolism, they do help prevent muscle loss and may increase energy levels. Some experts also suggest avoiding sugar, which can lead to excess fat storage. Spicy foods and green tea might also be beneficial.

Because stress activates cortisol release, and cortisol slows metabolism, avoiding stress, or at least practicing relaxation techniques, can also help.

Metabolic enzymes catalyze catabolic reactions that break down carbohydrates contained in food. The energy released is used to power the cells and systems that make up your body.

Excess or unutilized energy is stored as fat or glycogen for later use. Carbohydrate metabolism begins in the mouth, where the enzyme salivary amylase begins to break down complex sugars into monosaccharides.

These can then be transported across the intestinal membrane into the bloodstream and then to body tissues. In the cells, glucose, a six-carbon sugar, is processed through a sequence of reactions into smaller sugars, and the energy stored inside the molecule is released. The first step of carbohydrate catabolism is glycolysis, which produces pyruvate, NADH, and ATP.

Under anaerobic conditions, the pyruvate can be converted into lactate to keep glycolysis working. Under aerobic conditions, pyruvate enters the Krebs cycle, also called the citric acid cycle or tricarboxylic acid cycle.

In addition to ATP, the Krebs cycle produces high-energy FADH 2 and NADH molecules, which provide electrons to the oxidative phosphorylation process that generates more high-energy ATP molecules.

For each molecule of glucose that is processed in glycolysis, a net of 36 ATPs can be created by aerobic respiration.

Under anaerobic conditions, ATP production is limited to those generated by glycolysis. While a total of four ATPs are produced by glycolysis, two are needed to begin glycolysis, so there is a net yield of two ATP molecules.

In conditions of low glucose, such as fasting, starvation, or low carbohydrate diets, glucose can be synthesized from lactate, pyruvate, glycerol, alanine, or glutamate.

This process, called gluconeogenesis, is almost the reverse of glycolysis and serves to create glucose molecules for glucose-dependent organs, such as the brain, when glucose levels fall below normal.

salivary amylase: digestive enzyme that is found in the saliva and begins the digestion of carbohydrates in the mouth. cellular respiration: production of ATP from glucose oxidation via glycolysis, the Krebs cycle, and oxidative phosphorylation. glycolysis: series of metabolic reactions that breaks down glucose into pyruvate and produces ATP.

pyruvate: three-carbon end product of glycolysis and starting material that is converted into acetyl CoA that enters the. Krebs cycle: also called the citric acid cycle or the tricarboxylic acid cycle, converts pyruvate into CO 2 and high-energy FADH 2 , NADH, and ATP molecules. citric acid cycle or tricarboxylic acid cycle TCA : also called the Krebs cycle or the tricarboxylic acid cycle; converts pyruvate into CO 2 and high-energy FADH 2 , NADH, and ATP molecules.

energy-consuming phase , first phase of glycolysis, in which two molecules of ATP are necessary to start the reaction. glucosephosphate: phosphorylated glucose produced in the first step of glycolysis. Hexokinase: cellular enzyme, found in most tissues, that converts glucose into glucosephosphate upon uptake into the cell.

Glucokinase: cellularenzyme, found in the liver, which converts glucose into glucosephosphate upon uptake into the cell. energy-yielding phase: second phase of glycolysis, during which energy is produced.

terminal electron acceptor: ATP production pathway in which electrons are passed through a series of oxidation-reduction reactions that forms water and produces a proton gradient. electron transport chain ETC : ATP production pathway in which electrons are passed through a series of oxidation-reduction reactions that forms water and produces a proton gradient.

If we turn our attention to glucose from the bloodstream, as a source of energy for contracting the muscle, we see again that both exercise intensity and duration impact on the rate of glucose uptake. You can see in this graph, the glucose uptake into contracting leg muscles at three exercise intensities.

So, like this, an increased intensity, an increase in glucose uptake, and you also see that at any given exercise intensity, a progressive increase in glucose uptake.

If the exercise extends for several hours, then over time, what one sees is a slow reduction in glucose uptake as the blood glucose levels decline. This is one of the reasons why ingesting carbohydrate-containing drinks is often used as a strategy by endurance athletes to maintain blood glucose levels and to maintain glucose uptake during prolonged exercise.

In terms of the regulation of glucose uptake into muscle, we need to remember that this process occurs by facilitated diffusion and what that means is that we need a gradient for glucose to move from outside the muscle to inside the muscle.

We need a special transport carrier molecule to help get glucose across the membrane. There are three main sites of regulation for muscle glucose uptake: the supply of glucose, the transport of glucose across, the plasma membrane by a protein that we know as GLUT4, and the intracellular metabolism of glucose, during exercise with a large increase in muscle blood flow we see increase glucose delivery to the muscle.

In the post-exercise period, a very important process is the recovery of muscle glycogen. The re-synthesis of glycogen is the major metabolic fate of glucose that is taken up in the recovery period.

Ingesting carbohydrates during recovery is an important way of maximizing the re-synthesis of glycogen during recovery. The GLUT4 transport protein, which normally resides inside the muscle cell moves quickly to the plasma membrane where it becomes a functioning glucose transporter.

Finally, as I said, if you increase the disposal of glucose through glycolytic oxidative pathways that will maintain the diffusion gradient into the contracting skeletal muscle.

We know that the availability of other substrates will influence glucose uptake. If glycogen levels are high in the muscle we tend to see a lower glucose uptake. The availability of glucose in the bloodstream is very important because it sets the arterial glucose concentration for that diffusion gradient.

So, if glucose levels are low during prolonged exercise, in the absence of glucose ingestion, you will tend to see a decrease in glucose uptake, and if you increase the blood glucose level by ingesting a carbohydrate drink and absorbing the glucose from the gut, you will see an increase in glucose uptake.

The effects of free fatty acids on glucose uptake are a little less clear compared with those on muscle glycogen. With some studies suggesting that increased fatty acid availability will slow glucose uptake, other studies have seen no effect.

The important point to make in relation to glucose uptake during exercise is that it occurs independently of insulin.

The processes that are involved in glucose uptake during muscle contractions are slightly different from those involved with insulin stimulation. Another important consideration is that if you are Type I diabetic and you have to inject yourself with insulin. If that occurs in close proximity to exercise because the two stimuli are additive that can often increase the risk of premature hypoglycemia.

Given that the translocation of GLUT4 from inside the muscle cell to the sarcolemma is very important in removing the plasma membrane as a barrier for glucose uptake. You can see in this slide a number of molecules and enzymes that have been implicated in this GLUT4 translocation process.

Most attention has focused on two pretty fundamental changes in muscle. We spoke about those in the adaptations lecture, and that is the increase in calcium, and the change in energy status, which has an impact on a kinase, the ANP activated protein kinase.

So again, local events in the muscle changes in calcium and changes in the energy levels within the muscle serve to stimulate GLUT4 translocation to facilitate glucose uptakes in the contracting muscle during exercise.

Just as we saw with muscle glycogen neutralization after training, we also see a reduction in the reliance on glucose. This study was done using labeled isotopes of glucose, which enable you to measure glucose uptake and also the appearance of the carbon label in the expired breath, so you can measure oxidation.

You can see that both glucose uptake and glucose oxidation, are reduced, after endurance training. This is the role of the liver during exercise. You can see here that the curves for liver glucose output are very similar to those with muscle glucose uptake.

With an increase in exercise intensity and an increase in exercise, the duration will increase liver glucose output. You will note at the lower intensities here were the exercise duration is extended that eventually the liver is unable to maintain the same rate of glucose output and it starts to decline.

We see both feeds forward and feedback mechanisms. There are changes in the pancreatic hormones during exercise, insulin levels tend to go down and glucagon levels tend to go up and restored these two signals playing the important role in allowing the liver to increase its glucose output during exercise.

Circulating adrenaline can also act on the liver glycogen stores, which are then broken down to liberate glucose. The sympathetic nerves are thought to play a role although there have been some interesting experiments in patients who have had liver transplants and therefore the nerves to the liver have been cut.

So, I think this demonstrates if you like the redundancy and usually when there are multiple mechanisms controlling a process, it means that that process is quite important.

And we often see that in physiology with a number of regulatory control systems. Just like the muscle, if the liver glycogen store is increased. You tend to break down liver glycogen during exercise and have a higher liver glucose output.

The primary feedback control of liver glucose output is the blood glucose concentration. So, if it increases, you tend to reduce the liver glucose output. There are two processes that the liver utilizes to produce glucose, it can break down glycogen and this is referred to as glycogenolysis or it can also take various metabolites produced during exercises such as lactate, glycerol and some amino acids, and convert it to glucose in a process known as gluconeogenesis.

You can see in the left panel here, before training, the relative contribution of glycogenolysis and gluconeogenesis to the total liver glucose output.

Interestingly that reduction occurs in both glycogenolysis and in gluconeogenesis. Glucose from the bloodstream and glucose units derived from muscle glycogen is broken down during a series of reactions that we know as glycolysis to produce pyruvate.

This pyruvate has two main fates: it can either be converted to acetylcholine and enter the Krebs Cycle and be oxidized or it can be converted to lactate.

In terms of the oxidation of pyruvate, the important enzyme, which regulates the oxidation of pyruvate and therefore the rate of carbohydrate oxidation is called pyruvate dehydrogenase. You can see in this slide that again, intensity and duration a major determinants of pyruvate dehydrogenase PDH activity.

The other side of pyruvate is converted to lactate, and a curve that is quite well known is the increase in lactate with exercise of increasing intensity, and you can see in the left panel the exponential rise in lactate as you increase exercise intensity and this is related in part to the increased rate of glycogen breakdown.

Whereas when you exercise above the lactate threshold, you can see a steady rise in the blood lactate levels.