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

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 Arroum, Miguel A. Rosa, Dipanwita Dutta Chowdhury, Icksoo Lee, Joseph S. Brunzelle, Thomas H. Sanderson, Moh H. Malek, David Meierhofer, Brian F. P. Edwards, Irene Díaz-Moreno () and Maik Hüttemann ()
Additional contact information
Paul T. Morse: Wayne State University
Gonzalo Pérez-Mejías: Universidad de Sevilla - CSIC
Junmei Wan: Wayne State University
Alice A. Turner: 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
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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39820-8

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