MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival

• Published in: Cell death & disease 2014-04, Vol.5 (4), p.e1172-e1172
• Main Authors: Park, Y-Y, Nguyen, O T K, Kang, H, Cho, H
• Format: Article
• Language: English
• Subjects: 631/80/458/1275; 631/80/458/582; 631/80/474/1768; 631/80/642/333; Acetylation - drug effects; Amino Acid Sequence; Animals; Antibodies; Antimycin A - analogs & derivatives; Antimycin A - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Death - drug effects; Cell Survival - drug effects; Cytoprotection - drug effects; Gene Knockout Techniques; GTP Phosphohydrolases - chemistry; GTP Phosphohydrolases - metabolism; HeLa Cells; Homeostasis - drug effects; Humans; Immunology; Life Sciences; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - metabolism; Molecular Sequence Data; Mutant Proteins - metabolism; Original; original-article; Protein Binding - drug effects; Proteolysis - drug effects; Stress, Physiological - drug effects; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.142

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.