Journal
CELL RESEARCH
Volume 24, Issue 4, Pages 482-496Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2014.20
Keywords
mitochondrial fusion; mitofusin1/2; deubiquitinase USP30; 15-Oxospiramilactone
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Funding
- Natural Science Foundation of China (NSFC) [91213304, 81130045]
- Ministry of Sciences and Technology [2011CB910903, 2010CB912204]
- NSFC-joint foundation of Yunnan Province [U1032603]
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Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of S3. The inhibition of USP30 by S3 leads to an increase of non-degradative ubiquitination of Mfn1/2, which enhances Mfn1 and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.
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