The Krebs cycle, also known as the TCA or citric acid cycle, takes place within the mitochondrial matrix. In this cycle, acetyl CoA, derived from various metabolic pathways, enters and undergoes a series of reactions that fully oxidize it to carbon dioxide.
Each acetyl CoA molecule that enters the cycle generates three molecules of NADH, one molecule of FADH₂, and one molecule of ATP (or GTP).
Additionally, coenzyme A is regenerated during the cycle’s initial steps, allowing the process to continue.
The cycle is tightly regulated; high levels of ATP and NADH, which signal sufficient cellular energy, inhibit the cycle, thereby maintaining energy homeostasis.
Citric acid cycle with intermediates and energy output
Electron transport chain (ETC) and oxidative phosphorylation
The electron transport chain (ETC) and oxidative phosphorylation occur along the inner mitochondrial membrane, specifically within the cristae. Here, the high-energy electrons from NADH and FADH2 products of the Krebs cycle—are transferred through a series of redox reactions involving components such as FMN, Coenzyme Q, iron-sulfur clusters, and various cytochromes (including cytochrome b, c, and aa₃).
As electrons flow from NADH (the highest in energy) to oxygen (the lowest in energy), energy is released and used to pump protons from the mitochondrial matrix into the intermembrane space, creating an electrochemical proton gradient.
This proton motive force drives ATP synthase, which harnesses the energy of protons moving back into the matrix to convert ADP into ATP in a process called oxidative phosphorylation. The efficiency of this system is critical for energy production, but the ETC can be disrupted by certain inhibitors, including some antibiotics, cyanide, azide, and carbon monoxide.
Although NADH is the primary electron donor in the mitochondrial electron transport chain, NADPH is also vital. Generated mainly by the pentose phosphate pathway, NADPH acts as a reducing agent in biosynthetic reactions and antioxidant defenses, helping to maintain the cellular redox balance and enhance electron transport efficiency under stress.
Flavoproteins are enzymes that contain flavin cofactors (FAD or FMN), which allow them to participate in redox reactions by accepting and donating electrons. For instance, in Complex II of the electron transport chain, FAD accepts electrons from succinate oxidation and transfers them to ubiquinone, linking the citric acid cycle with oxidative phosphorylation for ATP production.
Oxidative phosphorylation
Oxidative phosphorylation is the process by which mitochondria convert electron energy into ATP. ATP synthase generates ATP as protons flow down their concentration gradient—a process known as chemiosmotic coupling. The electron transport chain pumps protons from the mitochondrial matrix into the intermembrane space, creating a proton motive force (PMF) that drives ATP synthesis as protons return to the matrix.
Under optimal conditions, the complete oxidation of one glucose molecule yields about 30-32 ATP, reflecting the tight coupling between the electron transport chain and ATP synthesis. This process is regulated by factors such as ADP availability, substrate levels, oxygen concentration, and ATP feedback.
Additionally, mitochondria influence cell fate via apoptosis, as disruptions in oxidative phosphorylation can produce reactive oxygen species (ROS) that trigger oxidative stress and cell death.
Electron transport chain and chemiosmotic ATP production
Metabolism of fatty acids and proteins
Metabolism of fats
Fats are digested in the small intestine These components are packaged into chylomicrons for transport through the lymphatic system and bloodstream, delivering lipids to tissues. Initially, ester hydrolysis by lipases in the cytosol converts triglycerides into free fatty acids and glycerol. Each fatty acid is then “activated” by forming a thioester bond with CoA, a reaction that requires ATP.
In β-oxidation, these acyl-CoA molecules are sequentially cleaved into two-carbon units of acetyl-CoA, generating FADH2 and NADH in the process. Acetyl-CoA enters the Krebs cycle, while FADH2 and NADH deliver electrons to the electron transport chain, ultimately driving ATP synthesis. Per gram, fats yield more energy than any other macronutrient.
β-oxidation of fatty acids
In the liver, when carbohydrate availability is low, excess acetyl-CoA can form ketone bodies(acetoacetate, β-hydroxybutyrate), which serve as alternative energy sources for tissues such as the brain.
Saturated and unsaturated fats
Saturated fatty acids have no carbon–carbon double bonds
Unsaturatedfatty acids contain one or more double bonds, affecting their fluidity and metabolic processing.
Anabolism/synthesis of fats
In addition to catabolism, cells can perform anabolism of fats, synthesizing fatty acids and triglycerides from acetyl-CoA. This represents a form of non-template synthesis, where complex biomolecules like lipids (and polysaccharides) are built without following a nucleic-acid-encoded template. These processes allow cells to store energy, maintain membrane integrity, and modulate signaling pathways.
Metabolism of proteins
Proteins are hydrolyzed into amino acids by peptidases, and the amino groups are converted into nitrogenous waste such as urea (or uric acid in certain species).
The remaining carbon skeleton can become pyruvate, acetyl-CoA, or other metabolic intermediates, depending on the amino acid. These carbon skeletons can fuel the Krebs cycle or serve as substrates for gluconeogenesis, thus integrating protein catabolism with the cell’s broader energy and biosynthetic pathways.
Hormonal regulation and integration of metabolism
Hormones regulate the body’s metabolic balance by signaling when to store fuel and when to mobilize it, ensuring tissues receive energy according to their needs. In this framework, both hormone structure (peptide, steroid, or amino-acid derived) and tissue-specific metabolism guide how different cells respond to signals.
For instance, the pancreas secretes insulin (a peptide hormone) in response to elevated blood glucose, prompting tissues—especially muscle and adipose—to take up glucose and store it as glycogen or fat. Conversely, glucagon (also from the pancreas) acts during low blood sugar by stimulating glycogenolysis and gluconeogenesis in the liver, raising circulating glucose levels.
Epinephrine and cortisol
Further integration comes from hormones like
Epinephrine (adrenaline), which accelerates glycogen breakdown in muscle during acute stress
Cortisol, a steroid hormone that adjusts protein and fat
Catabolism and upregulates gluconeogenesis over longer periods.
Muscle primarily uses glucose for quick ATP production
Adipose stores excess energy as triglycerides
The liver coordinates overall fuel distribution, converting substrates (e.g., amino acids, lactate, glycerol) into glucose or ketone bodies as needed.
Hormonal regulation of fuel metabolism
Hormonal regulation also shapes fuel metabolism across feeding, fasting, and exercise states. In fed conditions, insulin dominates, enabling glucose uptake and storage. In fasting or exercise, glucagon and epinephrine rise, mobilizing glycogen and fatty acids to sustain blood glucose and energy output.
Obesity and regulation of body mass
Chronic energy imbalance can lead to obesity—characterized by increased adipose tissue mass. This state triggers further hormonal dysregulation, sometimes diminishing insulin sensitivity and contributing to metabolic syndrome.
Both genetic factors and hormonal feedback loops (e.g., involving leptin and ghrelin, which regulate hunger and satiety) play roles in regulating body mass, underscoring how integrated hormonal signals maintain or disrupt energy homeostasis.
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