Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells
Damaged mitochondria can be removed by mitophagy, but how this organelle is recognized by the autophagy machinery is unclear. Chen and colleagues show that FUNDC1, an integral mitochondrial outer membrane protein, interacts with light chain 3 (LC3) and is essential for hypoxia-induced mitophagy. Acc...
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| Veröffentlicht in: | Nature cell biology 2012-02, Vol.14 (2), p.177-185 |
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| creator | Liu, Lei Feng, Du Chen, Guo Chen, Ming Zheng, Qiaoxia Song, Pingping Ma, Qi Zhu, Chongzhuo Wang, Rui Qi, Wanjun Huang, Lei Xue, Peng Li, Baowei Wang, Xiaohui Jin, Haijing Wang, Jun Yang, Fuquan Liu, Pingsheng Zhu, Yushan Sui, Senfang Chen, Quan |
| description | Damaged mitochondria can be removed by mitophagy, but how this organelle is recognized by the autophagy machinery is unclear. Chen and colleagues show that FUNDC1, an integral mitochondrial outer membrane protein, interacts with light chain 3 (LC3) and is essential for hypoxia-induced mitophagy.
Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells. |
| doi_str_mv | 10.1038/ncb2422 |
| format | Article |
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Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/ncb2422</identifier><identifier>PMID: 22267086</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/45/612/1240 ; 631/80/39/2348 ; 692/1807/244 ; Amino Acid Sequence ; Animals ; Autophagy ; Binding Sites - genetics ; Biomedical and Life Sciences ; Blotting, Western ; Cancer Research ; Causes of ; Cell Biology ; Cell Hypoxia ; Cell Line, Tumor ; Cells, Cultured ; Cellular proteins ; Complications and side effects ; Developmental Biology ; Genetic aspects ; Green Fluorescent Proteins - genetics ; Green Fluorescent Proteins - metabolism ; HeLa Cells ; Humans ; Hypoxia ; letter ; Life Sciences ; Mammals ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Metabolic disorders ; Metabolism ; Mice ; Mice, Inbred C57BL ; Microscopy, Fluorescence ; Microscopy, Immunoelectron ; Microtubule-Associated Proteins - genetics ; Microtubule-Associated Proteins - metabolism ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - ultrastructure ; Mitochondrial diseases ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Molecular Sequence Data ; Mutation ; Phagocytosis ; Phosphorylation ; Physiological aspects ; Protein Binding ; Proteins ; Quality control ; RNA Interference ; Sequence Homology, Amino Acid ; Stem Cells ; Three dimensional imaging</subject><ispartof>Nature cell biology, 2012-02, Vol.14 (2), p.177-185</ispartof><rights>Springer Nature Limited 2012</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-7b2e941f2d43f52d6e8fb6cbfe02b180617c6ff00d6509a008c6b2634ad581e03</citedby><cites>FETCH-LOGICAL-c508t-7b2e941f2d43f52d6e8fb6cbfe02b180617c6ff00d6509a008c6b2634ad581e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ncb2422$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ncb2422$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22267086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Lei</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><creatorcontrib>Chen, Guo</creatorcontrib><creatorcontrib>Chen, Ming</creatorcontrib><creatorcontrib>Zheng, Qiaoxia</creatorcontrib><creatorcontrib>Song, Pingping</creatorcontrib><creatorcontrib>Ma, Qi</creatorcontrib><creatorcontrib>Zhu, Chongzhuo</creatorcontrib><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Qi, Wanjun</creatorcontrib><creatorcontrib>Huang, Lei</creatorcontrib><creatorcontrib>Xue, Peng</creatorcontrib><creatorcontrib>Li, Baowei</creatorcontrib><creatorcontrib>Wang, Xiaohui</creatorcontrib><creatorcontrib>Jin, Haijing</creatorcontrib><creatorcontrib>Wang, Jun</creatorcontrib><creatorcontrib>Yang, Fuquan</creatorcontrib><creatorcontrib>Liu, Pingsheng</creatorcontrib><creatorcontrib>Zhu, Yushan</creatorcontrib><creatorcontrib>Sui, Senfang</creatorcontrib><creatorcontrib>Chen, Quan</creatorcontrib><title>Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Damaged mitochondria can be removed by mitophagy, but how this organelle is recognized by the autophagy machinery is unclear. Chen and colleagues show that FUNDC1, an integral mitochondrial outer membrane protein, interacts with light chain 3 (LC3) and is essential for hypoxia-induced mitophagy.
Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.</description><subject>631/45/612/1240</subject><subject>631/80/39/2348</subject><subject>692/1807/244</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Binding Sites - genetics</subject><subject>Biomedical and Life Sciences</subject><subject>Blotting, Western</subject><subject>Cancer Research</subject><subject>Causes of</subject><subject>Cell Biology</subject><subject>Cell Hypoxia</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Cellular proteins</subject><subject>Complications and side effects</subject><subject>Developmental Biology</subject><subject>Genetic aspects</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Mammals</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Metabolic disorders</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microscopy, Fluorescence</subject><subject>Microscopy, Immunoelectron</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - ultrastructure</subject><subject>Mitochondrial diseases</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Phagocytosis</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Quality control</subject><subject>RNA Interference</subject><subject>Sequence Homology, Amino Acid</subject><subject>Stem Cells</subject><subject>Three dimensional imaging</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkc1u1DAUhS0EoqUg3gBFYgEsUmwnceJlNVCoVEACuo78cz3jKrantiN13oZn4clw6PAzCHlhy_7uuef4IvSU4FOCm-G1V5K2lN5Dx6TtWd2ynt9fzqyr-4bTI_QopWuMSdvi_iE6opSyHg_sGMkPNge1CV5HK6YqzBli7cDJKDxU2xgyWF-dX318syKVA21FhlRtdttwa0VtvZ4V6MoVke1GrHdVgZ1wTkxW-O_fFExTeoweGDEleLLfT9DV-duvq_f15ad3F6uzy1p1eMh1Lynwlhiq28Z0VDMYjGRKGsBUkgEz0itmDMaadZgLjAfFJGVNK3Q3EMDNCXpxp1tc38yQ8uhsWhyUJGFOIyecl0pGC_n8H_I6zNEXc-Pym5x0TcP_UGsxwWi9CTkKtWiOZ3TAmNO-W7qe_ocqS4OzKngwttwfFLw6KChMhtu8FnNK48WXz4fsPpKKIaUIZtxG60TcFZ8_rY77wRfy2T7SLMuYfnO_Jl2Al3dAKk9-DfHvzIdaPwB_trQN</recordid><startdate>20120201</startdate><enddate>20120201</enddate><creator>Liu, Lei</creator><creator>Feng, Du</creator><creator>Chen, Guo</creator><creator>Chen, Ming</creator><creator>Zheng, Qiaoxia</creator><creator>Song, Pingping</creator><creator>Ma, Qi</creator><creator>Zhu, Chongzhuo</creator><creator>Wang, Rui</creator><creator>Qi, Wanjun</creator><creator>Huang, Lei</creator><creator>Xue, Peng</creator><creator>Li, Baowei</creator><creator>Wang, Xiaohui</creator><creator>Jin, Haijing</creator><creator>Wang, Jun</creator><creator>Yang, Fuquan</creator><creator>Liu, Pingsheng</creator><creator>Zhu, Yushan</creator><creator>Sui, Senfang</creator><creator>Chen, Quan</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20120201</creationdate><title>Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells</title><author>Liu, Lei ; Feng, Du ; Chen, Guo ; Chen, Ming ; Zheng, Qiaoxia ; Song, Pingping ; Ma, Qi ; Zhu, Chongzhuo ; Wang, Rui ; Qi, Wanjun ; Huang, Lei ; Xue, Peng ; Li, Baowei ; Wang, Xiaohui ; Jin, Haijing ; Wang, Jun ; Yang, Fuquan ; Liu, Pingsheng ; Zhu, Yushan ; Sui, Senfang ; Chen, Quan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-7b2e941f2d43f52d6e8fb6cbfe02b180617c6ff00d6509a008c6b2634ad581e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>631/45/612/1240</topic><topic>631/80/39/2348</topic><topic>692/1807/244</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Binding Sites - genetics</topic><topic>Biomedical and Life Sciences</topic><topic>Blotting, Western</topic><topic>Cancer Research</topic><topic>Causes of</topic><topic>Cell Biology</topic><topic>Cell Hypoxia</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>Cellular proteins</topic><topic>Complications and side effects</topic><topic>Developmental Biology</topic><topic>Genetic aspects</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>letter</topic><topic>Life Sciences</topic><topic>Mammals</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Metabolic disorders</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microscopy, Fluorescence</topic><topic>Microscopy, Immunoelectron</topic><topic>Microtubule-Associated Proteins - genetics</topic><topic>Microtubule-Associated Proteins - 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Academic</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Lei</au><au>Feng, Du</au><au>Chen, Guo</au><au>Chen, Ming</au><au>Zheng, Qiaoxia</au><au>Song, Pingping</au><au>Ma, Qi</au><au>Zhu, Chongzhuo</au><au>Wang, Rui</au><au>Qi, Wanjun</au><au>Huang, Lei</au><au>Xue, Peng</au><au>Li, Baowei</au><au>Wang, Xiaohui</au><au>Jin, Haijing</au><au>Wang, Jun</au><au>Yang, Fuquan</au><au>Liu, Pingsheng</au><au>Zhu, Yushan</au><au>Sui, Senfang</au><au>Chen, Quan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>14</volume><issue>2</issue><spage>177</spage><epage>185</epage><pages>177-185</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>Damaged mitochondria can be removed by mitophagy, but how this organelle is recognized by the autophagy machinery is unclear. Chen and colleagues show that FUNDC1, an integral mitochondrial outer membrane protein, interacts with light chain 3 (LC3) and is essential for hypoxia-induced mitophagy.
Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22267086</pmid><doi>10.1038/ncb2422</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-7392 |
| ispartof | Nature cell biology, 2012-02, Vol.14 (2), p.177-185 |
| issn | 1465-7392 1476-4679 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_919950962 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 631/45/612/1240 631/80/39/2348 692/1807/244 Amino Acid Sequence Animals Autophagy Binding Sites - genetics Biomedical and Life Sciences Blotting, Western Cancer Research Causes of Cell Biology Cell Hypoxia Cell Line, Tumor Cells, Cultured Cellular proteins Complications and side effects Developmental Biology Genetic aspects Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism HeLa Cells Humans Hypoxia letter Life Sciences Mammals Membrane Proteins - genetics Membrane Proteins - metabolism Metabolic disorders Metabolism Mice Mice, Inbred C57BL Microscopy, Fluorescence Microscopy, Immunoelectron Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Mitochondria Mitochondria - metabolism Mitochondria - ultrastructure Mitochondrial diseases Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Molecular Sequence Data Mutation Phagocytosis Phosphorylation Physiological aspects Protein Binding Proteins Quality control RNA Interference Sequence Homology, Amino Acid Stem Cells Three dimensional imaging |
| title | Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T07%3A31%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mitochondrial%20outer-membrane%20protein%20FUNDC1%20mediates%20hypoxia-induced%20mitophagy%20in%20mammalian%C2%A0cells&rft.jtitle=Nature%20cell%20biology&rft.au=Liu,%20Lei&rft.date=2012-02-01&rft.volume=14&rft.issue=2&rft.spage=177&rft.epage=185&rft.pages=177-185&rft.issn=1465-7392&rft.eissn=1476-4679&rft_id=info:doi/10.1038/ncb2422&rft_dat=%3Cgale_proqu%3EA280092750%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1038915339&rft_id=info:pmid/22267086&rft_galeid=A280092750&rfr_iscdi=true |