期刊
MOLECULAR BIOLOGY OF THE CELL
卷 27, 期 2, 页码 349-359出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E15-09-0678
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资金
- National Institutes of Health (NIH) [R01 NS085165, R01 HL105239, U01 HL116321, R01 GM083131, R01 GM102177]
- American Heart Association [15SDG22100002]
- Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH
Ubiquitin-and proteasome-dependent outer mitochondrial membrane (OMM)associated degradation (OMMAD) is critical for mitochondrial and cellular homeostasis. However, the scope and molecular mechanisms of the OMMAD pathways are still not well understood. We report that the OMM-associated E3 ubiquitin ligase MARCH5 controls dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and cell sensitivity to stress-induced apoptosis. MARCH5 knockout selectively inhibited ubiquitination and proteasomal degradation of MiD49, a mitochondrial receptor of Drp1, and consequently led to mitochondrial fragmentation. Mitochondrial fragmentation in MARCH5-/-cells was not associated with inhibition of mitochondrial fusion or bioenergetic defects, supporting the possibility that MARCH5 is a negative regulator of mitochondrial fission. Both MARCH5 re-expression and MiD49 knockout in MARCH5-/-cells reversed mitochondrial fragmentation and reduced sensitivity to stress-induced apoptosis. These findings and data showing MARCH5-dependent degradation of MiD49 upon stress support the possibility that MARCH5 regulation of MiD49 is a novel mechanism controlling mitochondrial fission and, consequently, the cellular response to stress.
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