A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30
Mitocbondrial 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...
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| Veröffentlicht in: | Cell research 2014-04, Vol.24 (4), p.482-496 |
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| creator | Yue, Wen Chen, Ziheng Liu, Haiyang Yan, Chen Chen, Ming Feng, Du Yan, Chaojun Wu, Hao Du, Lei Wang, Yueying Liu, Jinhua Huang, Xiaohu Xia, Laixin Liu, Lei Wang, Xiaohui Jin, Haijing Wang, Jun Song, Zhiyin Hao, Xiaojiang Chen, Quan |
| description | Mitocbondrial 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 （$3） that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfnl or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of $3. The inhibition of USP30 by $3 leads to an increase of non-degradative ubiquitination of Mfnl/2, which enhances Mfnl 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. |
| doi_str_mv | 10.1038/cr.2014.20 |
| format | Article |
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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 （$3） that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfnl or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of $3. The inhibition of USP30 by $3 leads to an increase of non-degradative ubiquitination of Mfnl/2, which enhances Mfnl 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.</description><identifier>ISSN: 1001-0602</identifier><identifier>EISSN: 1748-7838</identifier><identifier>DOI: 10.1038/cr.2014.20</identifier><identifier>PMID: 24513856</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/80/313/2378 ; 631/80/458/582 ; 631/80/642/333 ; Animals ; Cell Biology ; Cells, Cultured ; Diterpenes - pharmacology ; DNA遗传 ; Enzyme Inhibitors - pharmacology ; Gene Knockout Techniques ; GTP Phosphohydrolases - genetics ; HeLa Cells ; Humans ; Life Sciences ; Mice ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial DNA ; Mitochondrial Dynamics - drug effects ; Mitochondrial Membrane Transport Proteins - genetics ; Mitochondrial Proteins - antagonists & inhibitors ; Mitochondrial Proteins - genetics ; Original ; original-article ; Oxidative Phosphorylation - drug effects ; Physiology ; Respiration ; Thiolester Hydrolases - antagonists & inhibitors ; Ubiquitin-Specific Proteases - antagonists & inhibitors ; 体功能 ; 分子 ; 天然 ; 泛素化 ; 神经元 ; 线粒体 ; 衍生物</subject><ispartof>Cell research, 2014-04, Vol.24 (4), p.482-496</ispartof><rights>Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 2014</rights><rights>Copyright Nature Publishing Group Apr 2014</rights><rights>Copyright © 2014 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 2014 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-38f8da17b7d9b3f85e18b2836dc1e46276c70d85ba22b79f27d302444c950acf3</citedby><cites>FETCH-LOGICAL-c535t-38f8da17b7d9b3f85e18b2836dc1e46276c70d85ba22b79f27d302444c950acf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://image.cqvip.com/vip1000/qk/85240X/85240X.jpg</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975501/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975501/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,41469,42538,51300,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24513856$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yue, Wen</creatorcontrib><creatorcontrib>Chen, Ziheng</creatorcontrib><creatorcontrib>Liu, Haiyang</creatorcontrib><creatorcontrib>Yan, Chen</creatorcontrib><creatorcontrib>Chen, Ming</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><creatorcontrib>Yan, Chaojun</creatorcontrib><creatorcontrib>Wu, Hao</creatorcontrib><creatorcontrib>Du, Lei</creatorcontrib><creatorcontrib>Wang, Yueying</creatorcontrib><creatorcontrib>Liu, Jinhua</creatorcontrib><creatorcontrib>Huang, Xiaohu</creatorcontrib><creatorcontrib>Xia, Laixin</creatorcontrib><creatorcontrib>Liu, Lei</creatorcontrib><creatorcontrib>Wang, Xiaohui</creatorcontrib><creatorcontrib>Jin, Haijing</creatorcontrib><creatorcontrib>Wang, Jun</creatorcontrib><creatorcontrib>Song, Zhiyin</creatorcontrib><creatorcontrib>Hao, Xiaojiang</creatorcontrib><creatorcontrib>Chen, Quan</creatorcontrib><title>A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30</title><title>Cell research</title><addtitle>Cell Res</addtitle><addtitle>Cell Research</addtitle><description>Mitocbondrial 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 （$3） that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfnl or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of $3. The inhibition of USP30 by $3 leads to an increase of non-degradative ubiquitination of Mfnl/2, which enhances Mfnl 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.</description><subject>631/80/313/2378</subject><subject>631/80/458/582</subject><subject>631/80/642/333</subject><subject>Animals</subject><subject>Cell Biology</subject><subject>Cells, Cultured</subject><subject>Diterpenes - pharmacology</subject><subject>DNA遗传</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Knockout Techniques</subject><subject>GTP Phosphohydrolases - genetics</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial Dynamics - drug effects</subject><subject>Mitochondrial Membrane Transport Proteins - genetics</subject><subject>Mitochondrial Proteins - antagonists & inhibitors</subject><subject>Mitochondrial Proteins - 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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 （$3） that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfnl or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of $3. The inhibition of USP30 by $3 leads to an increase of non-degradative ubiquitination of Mfnl/2, which enhances Mfnl 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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24513856</pmid><doi>10.1038/cr.2014.20</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell research, 2014-04, Vol.24 (4), p.482-496 |
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| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 631/80/313/2378 631/80/458/582 631/80/642/333 Animals Cell Biology Cells, Cultured Diterpenes - pharmacology DNA遗传 Enzyme Inhibitors - pharmacology Gene Knockout Techniques GTP Phosphohydrolases - genetics HeLa Cells Humans Life Sciences Mice Mitochondria - drug effects Mitochondria - metabolism Mitochondrial DNA Mitochondrial Dynamics - drug effects Mitochondrial Membrane Transport Proteins - genetics Mitochondrial Proteins - antagonists & inhibitors Mitochondrial Proteins - genetics Original original-article Oxidative Phosphorylation - drug effects Physiology Respiration Thiolester Hydrolases - antagonists & inhibitors Ubiquitin-Specific Proteases - antagonists & inhibitors 体功能 分子 天然 泛素化 神经元 线粒体 衍生物 |
| title | A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30 |
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