Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme

Alpha-ketoglutarate dehydrogenase (KGDH; EC 1.2.4.2) catalyzes the fourth step of the tricarboxylic acid (TCA) cycle and links carbohydrate, fatty acid and amino acid metabolism to the aerobic production of ATP. KGDH is classically viewed as indispensable to energy metabolism and strictly located to mitochondria. Therefore, it is generally thought that the loss of its activity has catastrophic consequences for mammalian cells. However, recent advances in molecular biology and redox biology tools coupled with the implementation of new genetically modified mouse lines and cultured cells knocked down for components of KGDH have revealed it is a multifunctional cellular enzyme that localizes to the mitochondria and nucleus where it uses superoxide (O₂^•-)/hydrogen peroxide (H₂O₂) and metabolites related to its catalysis (e.g., alpha-ketoglutarate (KG), succinyl-CoA, succinate) to control cell fate decisions. In addition, it has been revealed that over-stimulation of KGDH causes severe oxidative stress through the hyper-production of O₂^•-/H₂O₂ and disturbs cell signals and epigenome regulation, which has been linked to cancer cell transformation, metabolic diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), and inflammation. Furthermore, inhibition of KGDH with competitive inhibitors, redox modifications, or shRNAs has shown that the targeted disruption of the enzyme can alleviate these diseases. The aim of this review is to update the literature on KGDH. It is not just a TCA cycle enzyme anymore.