FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions

In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to r...

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Veröffentlicht in:The EMBO journal 2016-07, Vol.35 (13), p.1368-1384
Hauptverfasser: Wu, Wenxian, Lin, Chunxia, Wu, Keng, Jiang, Lei, Wang, Xiaojing, Li, Wen, Zhuang, Haixia, Zhang, Xingliang, Chen, Hao, Li, Shupeng, Yang, Yue, Lu, Yue, Wang, Jingjing, Zhu, Runzhi, Zhang, Liangqing, Sui, Senfang, Tan, Ning, Zhao, Bin, Zhang, Jingjing, Li, Longxuan, Feng, Du
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container_end_page 1384
container_issue 13
container_start_page 1368
container_title The EMBO journal
container_volume 35
creator Wu, Wenxian
Lin, Chunxia
Wu, Keng
Jiang, Lei
Wang, Xiaojing
Li, Wen
Zhuang, Haixia
Zhang, Xingliang
Chen, Hao
Li, Shupeng
Yang, Yue
Lu, Yue
Wang, Jingjing
Zhu, Runzhi
Zhang, Liangqing
Sui, Senfang
Tan, Ning
Zhao, Bin
Zhang, Jingjing
Li, Longxuan
Feng, Du
description In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. Synopsis In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission. FUNDC1 accumulates at the ER–mitochondrial contact site (MAM) by association with calnexin in response to hypoxia. FUNDC1 mediates mitochondrial fission in response to hypoxia. FUNDC1 binds to DRP1 for mitochondrial fission during hypoxia. FUNDC1 is the molecular link that integrates mitochondrial fission and mitophagy at the interface of the MAM. Graphical Abstract In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission.
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The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. Synopsis In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission. FUNDC1 accumulates at the ER–mitochondrial contact site (MAM) by association with calnexin in response to hypoxia. FUNDC1 mediates mitochondrial fission in response to hypoxia. FUNDC1 binds to DRP1 for mitochondrial fission during hypoxia. FUNDC1 is the molecular link that integrates mitochondrial fission and mitophagy at the interface of the MAM. Graphical Abstract In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.15252/embj.201593102</identifier><identifier>PMID: 27145933</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>London: Blackwell Publishing Ltd</publisher><subject>autophagy ; Calnexin - metabolism ; Cells, Cultured ; Cellular biology ; Dynamins ; EMBO07 ; EMBO20 ; EMBO21 ; Endoplasmic Reticulum - metabolism ; ER-mitochondrial contact site ; GTP Phosphohydrolases - metabolism ; Humans ; Hypoxia ; MAM ; Membrane Proteins - metabolism ; Microtubule-Associated Proteins - metabolism ; Mitochondria ; Mitochondrial Dynamics ; mitochondrial fission ; Mitochondrial Proteins - metabolism ; Mitophagy ; Protein Binding ; Proteins</subject><ispartof>The EMBO journal, 2016-07, Vol.35 (13), p.1368-1384</ispartof><rights>The Authors 2016</rights><rights>2016 The Authors</rights><rights>2016 The Authors.</rights><rights>2016 EMBO</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-2489-4702</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864280/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864280/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,729,782,786,887,1419,1435,27931,27932,41127,42196,45581,45582,46416,46840,51583,53798,53800</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.15252/embj.201593102$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27145933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Wenxian</creatorcontrib><creatorcontrib>Lin, Chunxia</creatorcontrib><creatorcontrib>Wu, Keng</creatorcontrib><creatorcontrib>Jiang, Lei</creatorcontrib><creatorcontrib>Wang, Xiaojing</creatorcontrib><creatorcontrib>Li, Wen</creatorcontrib><creatorcontrib>Zhuang, Haixia</creatorcontrib><creatorcontrib>Zhang, Xingliang</creatorcontrib><creatorcontrib>Chen, Hao</creatorcontrib><creatorcontrib>Li, Shupeng</creatorcontrib><creatorcontrib>Yang, Yue</creatorcontrib><creatorcontrib>Lu, Yue</creatorcontrib><creatorcontrib>Wang, Jingjing</creatorcontrib><creatorcontrib>Zhu, Runzhi</creatorcontrib><creatorcontrib>Zhang, Liangqing</creatorcontrib><creatorcontrib>Sui, Senfang</creatorcontrib><creatorcontrib>Tan, Ning</creatorcontrib><creatorcontrib>Zhao, Bin</creatorcontrib><creatorcontrib>Zhang, Jingjing</creatorcontrib><creatorcontrib>Li, Longxuan</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><title>FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. Synopsis In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission. FUNDC1 accumulates at the ER–mitochondrial contact site (MAM) by association with calnexin in response to hypoxia. FUNDC1 mediates mitochondrial fission in response to hypoxia. FUNDC1 binds to DRP1 for mitochondrial fission during hypoxia. FUNDC1 is the molecular link that integrates mitochondrial fission and mitophagy at the interface of the MAM. 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Lin, Chunxia ; Wu, Keng ; Jiang, Lei ; Wang, Xiaojing ; Li, Wen ; Zhuang, Haixia ; Zhang, Xingliang ; Chen, Hao ; Li, Shupeng ; Yang, Yue ; Lu, Yue ; Wang, Jingjing ; Zhu, Runzhi ; Zhang, Liangqing ; Sui, Senfang ; Tan, Ning ; Zhao, Bin ; Zhang, Jingjing ; Li, Longxuan ; Feng, Du</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i5642-3cbf9c0533d4b5ffd3ef7d4c846a10340cc55335babdbece5e9b1d65188c57c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>autophagy</topic><topic>Calnexin - metabolism</topic><topic>Cells, Cultured</topic><topic>Cellular biology</topic><topic>Dynamins</topic><topic>EMBO07</topic><topic>EMBO20</topic><topic>EMBO21</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>ER-mitochondrial contact site</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>MAM</topic><topic>Membrane Proteins - metabolism</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Mitochondria</topic><topic>Mitochondrial Dynamics</topic><topic>mitochondrial fission</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>Mitophagy</topic><topic>Protein Binding</topic><topic>Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Wenxian</creatorcontrib><creatorcontrib>Lin, Chunxia</creatorcontrib><creatorcontrib>Wu, Keng</creatorcontrib><creatorcontrib>Jiang, Lei</creatorcontrib><creatorcontrib>Wang, Xiaojing</creatorcontrib><creatorcontrib>Li, Wen</creatorcontrib><creatorcontrib>Zhuang, Haixia</creatorcontrib><creatorcontrib>Zhang, Xingliang</creatorcontrib><creatorcontrib>Chen, Hao</creatorcontrib><creatorcontrib>Li, Shupeng</creatorcontrib><creatorcontrib>Yang, Yue</creatorcontrib><creatorcontrib>Lu, Yue</creatorcontrib><creatorcontrib>Wang, Jingjing</creatorcontrib><creatorcontrib>Zhu, Runzhi</creatorcontrib><creatorcontrib>Zhang, Liangqing</creatorcontrib><creatorcontrib>Sui, Senfang</creatorcontrib><creatorcontrib>Tan, Ning</creatorcontrib><creatorcontrib>Zhao, Bin</creatorcontrib><creatorcontrib>Zhang, Jingjing</creatorcontrib><creatorcontrib>Li, Longxuan</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; 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The ER–mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. Synopsis In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission. FUNDC1 accumulates at the ER–mitochondrial contact site (MAM) by association with calnexin in response to hypoxia. FUNDC1 mediates mitochondrial fission in response to hypoxia. FUNDC1 binds to DRP1 for mitochondrial fission during hypoxia. FUNDC1 is the molecular link that integrates mitochondrial fission and mitophagy at the interface of the MAM. Graphical Abstract In response to hypoxia, mitophagy receptor FUNDC1 associates with ER‐resident protein calnexin and thereby accumulates at the ER–mitochondrial contact site; this allows for DRP‐1 recruitment and thus mitochondrial fission.</abstract><cop>London</cop><pub>Blackwell Publishing Ltd</pub><pmid>27145933</pmid><doi>10.15252/embj.201593102</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-2489-4702</orcidid><oa>free_for_read</oa></addata></record>
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subjects autophagy
Calnexin - metabolism
Cells, Cultured
Cellular biology
Dynamins
EMBO07
EMBO20
EMBO21
Endoplasmic Reticulum - metabolism
ER-mitochondrial contact site
GTP Phosphohydrolases - metabolism
Humans
Hypoxia
MAM
Membrane Proteins - metabolism
Microtubule-Associated Proteins - metabolism
Mitochondria
Mitochondrial Dynamics
mitochondrial fission
Mitochondrial Proteins - metabolism
Mitophagy
Protein Binding
Proteins
title FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions
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