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

Erika M. Palmieri, Ronald Holewinski, Christopher L. McGinity, Ciro L. Pierri, Nunziata Maio, Jonathan M. Weiss, Vincenzo Tragni, Katrina M. Miranda, Tracey A. Rouault, Thorkell Andresson, David A. Wink and Daniel W. McVicar ()
Additional contact information
Erika M. Palmieri: Cancer Innovation Laboratory, NCI-Frederick
Ronald Holewinski: Leidos Biomedical Research, Inc.
Christopher L. McGinity: Cancer Innovation Laboratory, NCI-Frederick
Ciro L. Pierri: University of Bari
Nunziata Maio: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Jonathan M. Weiss: Cancer Innovation Laboratory, NCI-Frederick
Vincenzo Tragni: University of Bari
Katrina M. Miranda: University of Arizona
Tracey A. Rouault: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Thorkell Andresson: Leidos Biomedical Research, Inc.
David A. Wink: Cancer Innovation Laboratory, NCI-Frederick
Daniel W. McVicar: Cancer Innovation Laboratory, NCI-Frederick

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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 Cys477 and Cys484, 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-40738-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40738-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-40738-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().