The tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle, is a central metabolic pathway for nearly all life forms. Named after citric acid, a tricarboxylic acid consumed and regenerated during the process, it plays a fundamental role in how cells process nutrients.
How the Cycle Generates Energy
The TCA cycle produces energy carriers for the cell, specifically NADH and FADH2, along with a small amount of direct ATP or GTP. This circular pathway processes acetyl-CoA, a two-carbon molecule derived from the breakdown of carbohydrates, fats, and proteins. The reactions occur within the mitochondrial matrix in eukaryotic cells.
The cycle begins when acetyl-CoA combines with a four-carbon molecule called oxaloacetate to form a six-carbon molecule, citrate. Through eight enzyme-catalyzed steps, citrate is progressively oxidized, releasing two carbon dioxide molecules per turn. During these oxidation reactions, electrons are removed from intermediate molecules and transferred to NAD+ and FAD, reducing them to NADH and FADH2.
For each acetyl-CoA molecule entering the cycle, three NADH and one FADH2 are generated. One molecule of ATP (or GTP) is also produced directly through substrate-level phosphorylation. These reduced coenzymes represent stored chemical energy utilized in subsequent energy-generating processes.
The Cycle as a Metabolic Crossroads
Beyond energy carrier production, the TCA cycle serves as a central metabolic hub, connecting the metabolism of carbohydrates, fats, and proteins. Its intermediates act as building blocks for the synthesis of other essential molecules. This allows the cell to adapt its metabolism based on energy demands and nutrient sources.
For instance, intermediates like alpha-ketoglutarate and oxaloacetate can be used in anabolism, the process of building larger molecules. Alpha-ketoglutarate can be converted into amino acids such as glutamate and glutamine, used to synthesize proteins. Oxaloacetate can be used to synthesize aspartate or glucose through gluconeogenesis.
Conversely, various catabolic pathways feed into the TCA cycle. Products from the breakdown of fats, such as fatty acids, convert into acetyl-CoA, which then enters the cycle. Certain amino acids, after being deaminated, transform into pyruvate or other TCA cycle intermediates, allowing their carbon skeletons to be oxidized for energy or used for synthesis. This constant exchange highlights the cycle’s dynamic position in cellular metabolism.
Unlocking More Energy: The Next Steps
The NADH and FADH2 produced by the TCA cycle are the primary energy carriers that proceed to the electron transport chain (ETC) and oxidative phosphorylation. These processes generate the vast majority of the cell’s ATP. The TCA cycle itself does not consume molecular oxygen directly, but its products require oxygen for maximal energy extraction.
Within the inner mitochondrial membrane, the electron transport chain consists of protein complexes that accept electrons from NADH and FADH2. As electrons move through these complexes, energy is released, pumping protons from the mitochondrial matrix into the intermembrane space. This creates an electrochemical gradient, a significant store of potential energy.
Oxidative phosphorylation then harnesses this proton motive force to produce ATP. Protons flow back into the mitochondrial matrix through ATP synthase. This flow drives ATP synthesis from ADP and inorganic phosphate. While the TCA cycle yields a small amount of ATP directly, the coupled electron transport chain and oxidative phosphorylation generate approximately 2.5 ATP molecules per NADH and 1.5 ATP molecules per FADH2, resulting in a substantially larger energy yield.