MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival.
Mitochondrial dynamics and quality control have a central role in the maintenance of cellular integrity. Mitochondrial ubiquitin ligase membrane-associated RING-CH (MARCH5) regulates mitochondrial dynamics. Here, we show that mitochondrial adaptation to stress is driven by MARCH5-dependent quality control on acetylated Mfn1. Under mitochondrial stress conditions, levels of Mfn1 were elevated twofold and depletion of Mfn1 sensitized these cells to apoptotic death. Interestingly, overexpression of Mfn1 also promoted cell death in these cells, indicating that a fine tuning of Mfn1 levels is necessary for cell survival. MARCH5 binds Mfn1 and the MARCH5-dependent Mfn1 ubiquitylation was significantly elevated under mitochondrial stress conditions along with an increase in acetylated Mfn1. The acetylation-deficient K491R mutant of Mfn1 showed weak interaction with MARCH5 as well as reduced ubiquitylation. Neither was observed in the acetylation mimetic K491Q mutant. In addition, MARCH5-knockout mouse embryonic fibroblast and MARCH5(H43W)-expressing HeLa cells lacking ubiquitin ligase activity experienced rapid cell death upon mitochondrial stress. Taken together, a fine balance of Mfn1 levels is maintained by MARCH5-mediated quality control on acetylated Mfn1, which is crucial for cell survival under mitochondria stress conditions.
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
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Park
1] Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea [2] Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Korea.
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Nguyen
Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
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Kang
1] Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea [2] Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Korea.
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D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; C032456:antimycin; D000968:Antimycin A; C515578:MARCHF5 protein, human; C581898:Marchf5 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C470017:Mfn1 protein, human