Ketoglutaratdehydrogenase

Ketoglutaratdehydrogenase, also known as alpha-ketoglutarate dehydrogenase (α-KGDH), is a mitochondrial enzyme complex that participates in the citric acid cycle. It catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA, releasing carbon dioxide and producing NADH. The reaction links the oxidation of nutrients to the production of reducing equivalents used in respiration.

The α-KGDH complex is a multisubunit enzyme consisting of three catalytic components designated E1, E2, and E3. E1, the alpha-ketoglutarate dehydrogenase, is thiamine pyrophosphate–dependent and initiates decarboxylation. E2, dihydrolipoamide succinyltransferase, transfers the resulting succinyl group to CoA. E3, dihydrolipoamide dehydrogenase, reoxidizes the lipoamide cofactors while reducing NAD+ to NADH. The complex requires several cofactors, including thiamine pyrophosphate, lipoic acid, CoA, flavin adenine dinucleotide (FAD), and NAD+.

In human cells, the complex resides in the mitochondrial matrix. It is encoded by multiple nuclear genes corresponding to the three catalytic components: OGDH for E1, DLST for E2, and DLD for E3. Regulation of α-KGDH activity reflects cellular energy status and cofactor availability; it is inhibited by high levels of NADH and succinyl-CoA and can be modulated by calcium in tissues with high energy demand.

Deficiencies or mutations affecting the OGDH, DLST, or DLD genes are rare but can cause metabolic disease, often presenting with neurodevelopmental delay, hypotonia, lactic acidosis, or seizures. Treatment is supportive and may include strategies to optimize mitochondrial function; thiamine supplementation can help if a thiamine-dependent step is impaired.