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Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
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Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
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Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
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Journal Article
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
2023
Overview
M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys
477
and Cys
484
, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.
Nitric oxide has been shown to target mitochondrial aconitase 2 and pyruvate dehydrogenase to reprogramme macrophage metabolism. Here, the authors extend these findings to show that lipoate is used to generate nitroxyl in this process.
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