Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit’s natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.

丙酮酸脱氢酶复合物（PDHC）和氧化戊二酸脱氢酶复合物（OGDC）属于线粒体α-酮酸脱氢酶家族，在细胞代谢中发挥着至关重要的作用。这些多亚基酶复合物使用共价连接至其 E2 亚基的硫辛臂将酰基转移至辅酶 A (CoA)。在这里，我们报告了一种能够显着抑制 PDHC 和 OGDC 的新机制：活性氮（RNS）可以共价修饰其硫辛臂上的硫醇，产生一系列阻碍催化活性的加合物。S -Nitroso-CoA 是 RNS 和 E2 亚基的天然底物 CoA 之间的产物，可以有效地将这些修饰传递到硫辛臂上。我们发现 RNS 介导的 PDHC 和 OGDC 抑制发生在经典巨噬细胞激活过程中，随着时间的推移，驱动细胞代谢的显着重新连接。这项工作提供了 RNS 和线粒体代谢之间的新机制联系，与 RNS 积累的许多生理和病理条件具有潜在相关性。