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Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle

Author

Listed:
  • Paul T. Morse

    (Wayne State University)

  • Gonzalo Pérez-Mejías

    (Universidad de Sevilla - CSIC)

  • Junmei Wan

    (Wayne State University)

  • Alice A. Turner

    (Wayne State University
    Wayne State University)

  • Inmaculada Márquez

    (Universidad de Sevilla - CSIC)

  • Hasini A. Kalpage

    (Wayne State University)

  • Asmita Vaishnav

    (Wayne State University)

  • Matthew P. Zurek

    (Wayne State University
    Wayne State University)

  • Philipp P. Huettemann

    (Wayne State University)

  • Katherine Kim

    (Wayne State University)

  • Tasnim Arroum

    (Wayne State University)

  • Miguel A. Rosa

    (Universidad de Sevilla - CSIC)

  • Dipanwita Dutta Chowdhury

    (Wayne State University)

  • Icksoo Lee

    (Dankook University)

  • Joseph S. Brunzelle

    (Northwestern University, Center for Synchrotron Research)

  • Thomas H. Sanderson

    (University of Michigan Medical School)

  • Moh H. Malek

    (Wayne State University)

  • David Meierhofer

    (Max Planck Institute for Molecular Genetics)

  • Brian F. P. Edwards

    (Wayne State University)

  • Irene Díaz-Moreno

    (Universidad de Sevilla - CSIC)

  • Maik Hüttemann

    (Wayne State University
    Wayne State University)

Abstract

Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.

Suggested Citation

  • Paul T. Morse & Gonzalo Pérez-Mejías & Junmei Wan & Alice A. Turner & Inmaculada Márquez & Hasini A. Kalpage & Asmita Vaishnav & Matthew P. Zurek & Philipp P. Huettemann & Katherine Kim & Tasnim Arrou, 2023. "Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39820-8
    DOI: 10.1038/s41467-023-39820-8
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    References listed on IDEAS

    as
    1. Alan K. Okada & Kazuki Teranishi & Mark R. Ambroso & Jose Mario Isas & Elena Vazquez-Sarandeses & Joo-Yeun Lee & Arthur Alves Melo & Priyatama Pandey & Daniel Merken & Leona Berndt & Michael Lammers &, 2021. "Lysine acetylation regulates the interaction between proteins and membranes," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Cuihong Wan & Blake Borgeson & Sadhna Phanse & Fan Tu & Kevin Drew & Greg Clark & Xuejian Xiong & Olga Kagan & Julian Kwan & Alexandr Bezginov & Kyle Chessman & Swati Pal & Graham Cromar & Ophelia Pap, 2015. "Panorama of ancient metazoan macromolecular complexes," Nature, Nature, vol. 525(7569), pages 339-344, September.
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