title: A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30.
abstract: 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.
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Wen
authors: W
authors: Yue
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ziheng
authors: Z
authors: Chen
authors: The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
authors: Haiyang
authors: H
authors: Liu
authors: The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
authors: Chen
authors: C
authors: Yan
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ming
authors: M
authors: Chen
authors: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors: Du
authors: D
authors: Feng
authors: College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors: Chaojun
authors: C
authors: Yan
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Hao
authors: H
authors: Wu
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Lei
authors: L
authors: Du
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Yueying
authors: Y
authors: Wang
authors: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors: Jinhua
authors: J
authors: Liu
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors: Xiaohu
authors: X
authors: Huang
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Laixin
authors: L
authors: Xia
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Lei
authors: L
authors: Liu
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Xiaohui
authors: X
authors: Wang
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Haijing
authors: H
authors: Jin
authors: Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Jun
authors: J
authors: Wang
authors: College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors: Zhiyin
authors: Z
authors: Song
authors: The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
authors: Xiaojiang
authors: X
authors: Hao
authors: 1] Laboratory of Apoptosis and Mitochondrial Biology, The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China [3] College of Life Sciences, Nankai University, Tianjin 300071, China.
authors: Quan
authors: Q
authors: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000235:genetics; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010085:Oxidative Phosphorylation / Q000187:drug effects; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors
chemical_list: C560615:15-oxospiramilactone; D004224:Diterpenes; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C532819:Usp30 protein, human; D013869:Thiolester Hydrolases; D064570:Ubiquitin-Specific Proteases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human