2-oxoglutarate dehydrogenase (OGDH)

2-oxoglutarate dehydrogenase (OGDH), commonly referred to as alpha-ketoglutarate dehydrogenase, is the rate-limiting E1 component of the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) [1, 10, 12]. It catalyzes the oxidative decarboxylation of 2-oxoglutarate into succinyl-CoA and CO2, a pivotal step in the tricarboxylic acid (TCA) cycle that generates NADH to fuel mitochondrial ATP production [3, 21]. Beyond its primary metabolic role in the mitochondria, a fraction of OGDH localizes to the nucleus, where it associates with chromatin to provide succinyl-CoA for histone succinylation, thereby influencing epigenetic regulation [21]. In clinical contexts, OGDH activity is frequently upregulated in various malignancies, such as pancreatic and ovarian cancer, to meet the high bioenergetic and biosynthetic demands of tumor growth [1, 7, 8]. Conversely, a marked decline in OGDH activity is characteristic of neurodegenerative disorders like Alzheimer's and Parkinson's diseases, where its dysfunction contributes to metabolic failure and elevated oxidative stress [12, 22]. As a therapeutic target, OGDH is primarily inhibited by the clinical-stage drug devimistat (CPI-613), a lipoate analog that selectively disrupts cancer cell metabolism by inactivating both the OGDH and pyruvate dehydrogenase complexes, ultimately leading to mitochondrial collapse and apoptosis [6, 9, 11].

Other names

Alpha-ketoglutarate dehydrogenaseα-ketoglutarate dehydrogenase2-oxoglutarate dehydrogenase complex component E1E1oAKGDH2-oxoglutarate dehydrogenase, mitochondrial

Inhibition of mitochondrial metabolism by blocking the conversion of 2-oxoglutarate to succinyl-CoA within the TCA cycle, often achieved through lipoate mimicry or hyperactivation of regulatory enzymes that inactivate the complex [1, 6, 9].