Alpha-ketoglutarate dehydrogenase (KGDH): an update on its redox regulation and importance in generating mitochondrial reactive oxygen species (mtROS) in hepatocytes.

The regulated production of mitochondrial reactive oxygen species (mtROS) is vital for maintaining optimal liver health. The mtROS-mediated maintenance of cell function(s) is through the induction of oxidative eustress signals, which are transmitted through the site-specific cysteine modifications. By contrast, the sustained overgeneration of mtROS triggers oxidative distress, resulting in the manifestation of metabolic diseases like non-alcoholic fatty liver disease (NAFLD) and the progression of cancer. Therefore, it is crucial to understand precisely how mitochondria generate mtROS, how its production is regulated, and how dysfunction in these regulatory mechanisms may cause NAFLD and its related disorders. Complexes I and III of the electron transport chain (ETC) are viewed as the primary mtROS sources in mammalian cells. However, we recently generated compelling evidence showing that TCA cycle enzyme α-ketoglutarate dehydrogenase (KGDH), and not the ETC, is the main mtROS supplier in hepatocytes. We found that KGDH is a main mtROS source when hepatic mitochondria are fueled with oxidizable substrates and is a main source of oxidative stress in the livers of mice subjected to dietary fat overload. Additionally, we discovered that mtROS generation by KGDH is controlled by reversible protein S-glutathionylation, which is catalyzed by glutaredoxin-2 (Glrx2). In this context, the oxidation of the glutathione (GSH) pool S-glutathionylates KGDH to shut down mtROS generation. This creates a self-contained negative feedback loop for the redox regulation of mtROS production. Recently, we showed that the manipulation of the Glrx2 pathway protects from diet-induced NAFLD development through the dynamic inhibition of KGDH-mediated mtROS hyper-generation by S-glutathionylation. In this presentation, I will elaborate on the importance of these findings in understanding the manifestation of NAFLD and how the targeted and dynamic redox modification of KGDH with mitochondria-targeted drugs can mitigate the onset of this disease through the dynamic inhibition of mtROS hyper-production by redox modifications.