Volume 24, No 4, Apr 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 4, April 2014: 482-496

ORIGINAL ARTICLES

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

Wen Yue^1,2,*, Ziheng Chen^1,2,*, Haiyang Liu³, Chen Yan³, Ming Chen^1,2, Du Feng⁴, Chaojun Yan⁶, Hao Wu^1,2, Lei Du^1,2, Yueying Wang^1,2, Jinhua Liu⁴, Xiaohu Huang⁵, Laixin Xia¹, Lei Liu¹, Xiaohui Wang¹, Haijing Jin¹, Jun Wang¹, Zhiyin Song⁶, Xiaojiang Hao³ and Quan Chen^1,2,4

¹Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
²University of Chinese Academy of Sciences, Beijing 100049, China
³The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
⁴College of Life Sciences, Nankai University, Tianjin 300071, China
⁵State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
⁶College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China Correspondence: Quan Chen, E-mail: chenq@ioz.ac.cn;Tel: +86-010-64807322; Xiaojiang Hao,Tel: +86-0871-5219684;(haoxj@mail.kib.ac.cn)

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.

10.1038/cr.2014.20

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