학술논문
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
Document Type
Academic Journal
Author
Palmieri EM; Cancer Innovation Laboratory, NCI-Frederick, Frederick, MD, 21702, USA.; Holewinski R; Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA.; McGinity CL; Cancer Innovation Laboratory, NCI-Frederick, Frederick, MD, 21702, USA.; Pierri CL; Laboratory of Biochemistry, Molecular and Structural Biology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Via E. Orabona, 4, Bari, 70125, Italy.; Maio N; Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, Bethesda, MD, 20892, USA.; Weiss JM; Cancer Innovation Laboratory, NCI-Frederick, Frederick, MD, 21702, USA.; Tragni V; Laboratory of Biochemistry, Molecular and Structural Biology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Via E. Orabona, 4, Bari, 70125, Italy.; Miranda KM; Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, USA.; Rouault TA; Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, Bethesda, MD, 20892, USA.; Andresson T; Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA.; Wink DA; Cancer Innovation Laboratory, NCI-Frederick, Frederick, MD, 21702, USA.; McVicar DW; Cancer Innovation Laboratory, NCI-Frederick, Frederick, MD, 21702, USA. mcvicard@mail.nih.gov.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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 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.
(© 2023. Springer Nature Limited.)
(© 2023. Springer Nature Limited.)