Mailloux Ryan J
School of Human Nutrition, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, Quebec, QC H9X 3V9, Canada.
Cells. 2025 Apr 29;14(9):653. doi: 10.3390/cells14090653.
α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through the reversible oxidation of the vicinal lipoic acid thiols of its dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls its activity and, by extension, OxPhos. This characteristic inculcates KGDHc with redox regulatory properties for the modulation of metabolism and mediating of intra- and intercellular signals. The innate capacity of KGDHc to participate in the regulation of cell redox homeodynamics also occurs through the production of mitochondrial hydrogen peroxide (mtHO), which is generated by the dihydrolipoamide dehydrogenase (DLD; E3) downstream from the E2 subunit. Reversible covalent redox modification of the E2 subunit controls this mtHO production by KGDHc, which not only protects from oxidative distress but also modulates oxidative eustress pathways. The importance of KGDHc in modulating redox homeodynamics is underscored by the pathogenesis of neurological and metabolic disorders that occur due to the hyper-generation of mtHO by this enzyme complex. This also implies that the targeted redox modification of the E2 subunit could be a potential therapeutic strategy for limiting the oxidative distress triggered by KGDHc mtHO hyper-generation. In this short article, I will discuss recent findings demonstrating KGDHc is a potent mtHO source that can trigger the manifestation of several neurological and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), inflammation, and cancer, and the targeted redox modification of the E2 subunit could alleviate these syndromes.
α-酮戊二酸脱氢酶复合体（KGDHc）是三羧酸（TCA）循环中的一种关键酶，它将单糖、氨基酸和脂肪酸分解代谢与氧化磷酸化（OxPhos）联系起来。KGDHc的一个关键特征是其能够通过其二氢硫辛酰胺琥珀酰转移酶（DLST；E2）亚基的邻位硫辛酸硫醇的可逆氧化来感知氧化还原环境的变化，这控制了它的活性，进而控制了氧化磷酸化。这一特性赋予KGDHc氧化还原调节特性，用于调节代谢以及介导细胞内和细胞间信号。KGDHc参与细胞氧化还原稳态调节的内在能力还通过线粒体过氧化氢（mtHO）的产生来实现，mtHO由E2亚基下游的二氢硫辛酰胺脱氢酶（DLD；E3）产生。E2亚基的可逆共价氧化还原修饰控制了KGDHc产生mtHO的过程，这不仅能保护细胞免受氧化应激，还能调节氧化应激通路。由于该酶复合体过度产生mtHO而导致的神经和代谢紊乱的发病机制凸显了KGDHc在调节氧化还原稳态中的重要性。这也意味着对E2亚基进行靶向氧化还原修饰可能是一种潜在的治疗策略，用于限制由KGDHc过度产生mtHO引发的氧化应激。在这篇短文中，我将讨论最近的研究发现，这些发现表明KGDHc是一种强大的mtHO来源，可引发包括非酒精性脂肪性肝病（NAFLD）、炎症和癌症在内的多种神经和代谢疾病的表现，而对E2亚基进行靶向氧化还原修饰可以缓解这些症状。
