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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & D, 2023. "Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40738-4
    DOI: 10.1038/s41467-023-40738-4
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    References listed on IDEAS

    as
    1. Erika M. Palmieri & Marieli Gonzalez-Cotto & Walter A. Baseler & Luke C. Davies & Bart Ghesquière & Nunziata Maio & Christopher M. Rice & Tracey A. Rouault & Teresa Cassel & Richard M. Higashi & Andre, 2020. "Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Mirjam Eberhardt & Maria Dux & Barbara Namer & Jan Miljkovic & Nada Cordasic & Christine Will & Tatjana I. Kichko & Jeanne de la Roche & Michael Fischer & Sebastián A. Suárez & Damian Bikiel & Karola , 2014. "H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway," Nature Communications, Nature, vol. 5(1), pages 1-17, September.
    3. Jana Škerlová & Jens Berndtsson & Hendrik Nolte & Martin Ott & Pål Stenmark, 2021. "Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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