Cellular Respiration

The reactants of cellular respiration vary at each stage, but initially, it requires an input of glucose, ATP, and NAD+. NAD+, a nicotinamide derived from vitamin B₃, is a universal electron acceptor that is crucial in the process of cellular respiration. Another important universal electron acceptor is FAD, a flavin nucleotide derived from vitamin B₂. These electron acceptors are often used in catabolic processes and are reduced into NADH and FADH₂, respectively. 

Specifically, glycolysis requires an input of glucose, 2 ATP and 2 NAD+. Reactants for pyruvate oxidation are pyruvate, NAD+, and coenzyme A (CoA). Next, the citric acid cycle requires acetyl-CoA, 1 ADP, 3 NAD+, and 1 FAD.  

Finally, the electron transport chain through the process of oxidative phosphorylation uses the reactants ADP, NADH, FADH₂, and O₂. 

The final end products of cellular respiration are ATP, CO₂, and H₂O. Glycolysis produces 2 pyruvate molecules, 2 ATP, 2 NADH, and 2 H₂O. Therefore, without the presence of oxygen, glycolysis is the only process that can occur, and only 2 ATP molecules can be produced for each glucose molecule. Fortunately, most cells have access to oxygen, so the products of glycolysis (i.e., 2 pyruvate and 2 NADH) can be used for further energy production in subsequent steps of cellular respiration. 

When oxygen is present, pyruvate oxidation produces 1 acetyl-CoA, 1 NADH, and 1 CO₂ per pyruvate molecule. The citric acid cycle then yields 1 GTP (i.e., an energy-rich compound similar to ATP used primarily in lower pH environments), 3 NADH, 1 FADH2, and 2 CO₂. Of course, because a single glucose molecule produces 2 pyruvate molecules, the yield of substrates through pyruvate oxidation and the citric acid cycle is doubled. 

Finally, all of the NADH and FADH₂ produced by the previous steps can be used by the electron transport chain to create further ATP as part of oxidative phosphorylation. In this step, each NADH yields approximately 2-3 ATP while each FADH2 yields 1-2 ATP. Counting up all of the end products of glucose metabolism results in a total of 10 NADH, 2 FAD, 2 GTP, and 2 ATP.  Thus, oxidative phosphorylation and the electron transport chain produce approximately 28 ATP per glucose molecule, resulting in a total of 32 ATP equivalents and a maximum theoretical yield of 38 ATP through cellular respiration.  

But, as it turns out, the NADH created in the cytosol during glycolysis must be transported into the mitochondria using a shuttle system, which results in less energy produced per cytosolic NADH. Therefore, the actual yield of cellular respiration ends up being around 30-32 ATP per glucose molecule.  

There are three primary rate-determining enzymes in cellular respiration. These enzymes are the key regulatory enzymes that control the speed of the metabolic pathway. They act as "bottlenecks," meaning they regulate the flow of reactions and ensure energy production is adjusted to the cell's needs.  

The rate determining enzyme in glycolysis is phosphofructokinase-1, or PFK-1, which converts fructose-6-phosphate to fructose-1,6-bisphosphate. PFK-1 is closely regulated by another enzyme called fructose-2,6-bisphosphate, or PFK-2. PFK-2 activity increases when blood glucose levels go up, so that more glucose can be turned into energy. At the same time PFK-1 activity is inhibited by ATP, which makes sense because cells that have lots of energy don’t need to generate even more. 

Pyruvate oxidation only uses pyruvate dehydrogenase, which is activated by increased NAD⁺, ADP, or Ca²⁺ to respond to increased demands in energy production. 

In the citric acid cycle, the rate determining enzyme is isocitrate dehydrogenase, which converts isocitrate to ɑ-ketoglutarate. The specific reaction is stimulated by ADP and inhibited by both ATP and NADH, indicating that the cell is in a high energy state.  

Several diseases can affect cellular respiration. Since cellular respiration is so vital to bodily functions, many of these diseases severely affect individuals. 

 The most common diseases affecting glycolysis are pyruvate kinase deficiency, erythrocyte hexokinase deficiency, and glucose phosphate isomerase deficiency. These diseases are typically inherited in an autosomal recessive manner and individuals who are homozygous (i.e., have two affected genes) for these diseases develop hemolytic anemia, jaundice, and splenomegaly.   

Deficiencies in the pyruvate dehydrogenase enzyme can interfere with pyruvate oxidation. These can result in lactic acidosis characterized by a build-up of lactate and increased serum alanine due to pyruvate build-up that then undergoes fermentation to lactic acid. Children born with these deficiencies may have neurological defects, and management of the disease typically includes keto-diets or diets high in fats which decrease the amount of glycolysis the body uses to function. 

There are several enzymes in the citric acid cycle that may be affected and result in disease, including succinyl-CoA synthase and fumarase. Many individuals with these disorders have involuntary muscle spasms and involuntary forced postures, called dystonia, and may be deaf. 

Mitochondrial myopathies are genetic disorders that affect the production of enzymes involved in the electron transport chain or oxidative phosphorylation. These diseases are classically characterized by muscle weakness and fatigue, as well as diabetes. 

Additionally, exposure to high amounts of certain drugs or toxic chemicals can affect the electron transport chain or oxidative phosphorylation. Substances that can directly inhibit complexes in the electron transport chain include carbon monoxide and cyanide. Other substances may inhibit ATP synthase, such as the antibiotic oligomycin, or disrupt the connection between the electron transport chain and ATP synthase (i.e., an electron transport chain uncoupler), such as aspirin or 2,4-dinitrophenol. Statins, which are a class of lipid-lowering medications don’t inhibit electron transport chain, but they can decrease the synthesis of coenzyme Q. That reduction in coenzyme Q can result in decreased ATP production and lead to muscle pains and cramps.