Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming

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 li...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2023-08, Vol.14 (1), p.5114-5114, Article 5114
Main Authors: Palmieri, Erika M., Holewinski, Ronald, McGinity, Christopher L., Pierri, Ciro L., Maio, Nunziata, Weiss, Jonathan M., Tragni, Vincenzo, Miranda, Katrina M., Rouault, Tracey A., Andresson, Thorkell, Wink, David A., McVicar, Daniel W.
Format: Article
Language:English
Subjects:
140/58
38/109
631/250
631/92/1643
64/60
96/106
Dehydrogenase
Dehydrogenases
Enzymes
Glycolysis
Humanities and Social Sciences
Macrophages
Metabolism
Molecular modelling
multidisciplinary
Mutagenesis
Nitric oxide
Pyruvic acid
Science
Science (multidisciplinary)
Thiols
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40738-4