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

Author:

Morse Paul T.ORCID,Pérez-Mejías GonzaloORCID,Wan Junmei,Turner Alice A.,Márquez InmaculadaORCID,Kalpage Hasini A.,Vaishnav Asmita,Zurek Matthew P.,Huettemann Philipp P.,Kim Katherine,Arroum TasnimORCID,De la Rosa Miguel A.ORCID,Chowdhury Dipanwita Dutta,Lee Icksoo,Brunzelle Joseph S.,Sanderson Thomas H.ORCID,Malek Moh H.,Meierhofer David,Edwards Brian F. P.ORCID,Díaz-Moreno IreneORCID,Hüttemann MaikORCID

Abstract

AbstractSkeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochromec(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 cytochromecoxidase (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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

EC | European Regional Development Fund

Universidad de Sevilla

Fundación Ramón Areces

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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