Modifications of lipoic arm by reactive nitrogen species regulate α-ketoacid dehydrogenases

Abstract Mitochondrial α-ketoacid dehydrogenases, including the pyruvate dehydrogenase complex (PDHC) and the oxoglutarate dehydrogenase complex (OGDC), are a family of multi-subunit enzyme complexes that use a lipoic arm to transfer an acyl group to coenzyme A (CoA). The regulation of α-ketoacid dehydrogenases plays crucial roles in mitochondrial metabolism and cellular energy homeostasis. We previously found that PDHC and OGDC become profoundly inhibited in macrophages upon classical activation, causing substantial remodeling of the TCA cycle. This inhibition was driven by the loss of the catalytically active lipoic moiety; however, the molecular mechanism causing this loss was not clear. Here we show that reactive nitrogen species (RNS), which are produced by activated macrophages, can cause a series of thiol-modifications to the lipoic arm that inactivate PDHC and OGDC. CoA-SNO, the non-enzymatic product between RNS and the E2 subunit’s natural substrate CoA, plays a key role in efficiently delivering RNS mediated modifications onto the lipoic arm. This work reveals a new biochemical mechanism capable of substantially regulating mitochondrial α-ketoacid dehydrogenases, which has potential relevance for a range of physiological and pathological conditions.