Mitochondrial 8-enzyme cycle oxidizing acetyl-CoA to 2 CO2 with reduction of 3 NAD+ + 1 FAD + 1 GDP → ATP-equivalents that drive the electron transport chain. Citrate synthase condenses acetyl-CoA + oxaloacetate; aconitase isomerizes; isocitrate dehydrogenase (rate-limiting, NAD-linked) + α-ketoglutarate dehydrogenase + succinyl-CoA synthetase + succinate dehydrogenase (also Complex II of ETC) + fumarase + malate dehydrogenase complete the cycle. Anaplerotic refilling primarily from pyruvate carboxylase (pyruvate → oxaloacetate) maintains intermediate pool during high biosynthesis demand.
Organ Systems
endocrine
musculoskeletal
Pathway Steps
acetyl-coa → citrate — via citrate synthase (irreversible). Citrate synthase condenses acetyl-CoA with oxaloacetate — the irreversible entry step, paced by oxaloacetate supply and inhibited by ATP, NADH, and citrate. Each acetyl-CoA turn ultimately yields 3 NADH, 1 FADH₂, and 1 GTP.
citrate → isocitrate — via aconitase. Aconitase isomerizes citrate to isocitrate via cis-aconitate. Its iron–sulfur cluster is poisoned by fluoroacetate (→ fluorocitrate) and, when the cluster is lost, the apoprotein moonlights as the cytosolic iron-regulatory protein IRP1.
isocitrate → alpha-ketoglutarate — via isocitrate dehydrogenase (IDH) — rate-limiting; NAD-linked. Isocitrate dehydrogenase is the rate-limiting, NAD⁺-linked step (mitochondrial IDH3), activated by ADP/Ca²⁺ and inhibited by ATP/NADH. The NADP⁺ isoforms IDH1/2, when mutated in gliomas and AML, produce the oncometabolite 2-hydroxyglutarate.
alpha-ketoglutarate → succinyl-coa — via α-KG dehydrogenase complex (mirror of PDH). The α-ketoglutarate dehydrogenase complex mirrors PDH — same five cofactors (thiamine/TPP, lipoate, FAD, NAD⁺, CoA) — and is a second NADH-yielding, irreversible control point inhibited by NADH and succinyl-CoA. Thiamine deficiency throttles it.
succinyl-coa → succinate — via succinyl-CoA synthetase (substrate-level phosphorylation). Succinyl-CoA synthetase performs the cycle’s only substrate-level phosphorylation, capturing the thioester bond energy as GTP (or ATP). Succinyl-CoA also branches off to heme synthesis and to ketone-body activation.
succinate → fumarate — via succinate dehydrogenase = ETC Complex II. Succinate dehydrogenase is the only TCA enzyme embedded in the inner membrane and doubles as electron-transport-chain Complex II, feeding FADH₂ electrons straight to ubiquinone. SDH-subunit mutations cause hereditary paraganglioma/pheochromocytoma.
fumarate → malate — via fumarase. Fumarase hydrates fumarate to L-malate. Fumarate also arrives here from the urea cycle (argininosuccinate lyase) and purine synthesis, linking those pathways into the TCA pool; fumarase loss is a recognized tumor-suppressor defect.
malate → oxaloacetate — via malate dehydrogenase (closes cycle). Malate dehydrogenase regenerates oxaloacetate and a third NADH, closing the cycle. The reaction is endergonic but pulled forward by citrate synthase consuming OAA; the malate–aspartate shuttle uses this couple to ferry cytosolic NADH equivalents into mitochondria.