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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10444860/ https://www.ncbi.nlm.nih.gov/pubmed/37607904 http://dx.doi.org/10.1038/s41467-023-40738-4 |
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author | 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. |
author_facet | 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. |
author_sort | Palmieri, Erika M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10444860 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104448602023-08-24 Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming 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. Nat Commun Article 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. Nature Publishing Group UK 2023-08-22 /pmc/articles/PMC10444860/ /pubmed/37607904 http://dx.doi.org/10.1038/s41467-023-40738-4 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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. Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title | Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title_full | Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title_fullStr | Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title_full_unstemmed | Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title_short | Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
title_sort | pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10444860/ https://www.ncbi.nlm.nih.gov/pubmed/37607904 http://dx.doi.org/10.1038/s41467-023-40738-4 |
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