The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake
The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the i...
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| Veröffentlicht in: | Cell metabolism 2015-10, Vol.22 (4), p.721-733 |
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| container_title | Cell metabolism |
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| creator | Petrungaro, Carmelina Zimmermann, Katharina M Küttner, Victoria Fischer, Manuel Dengjel, Jörn Bogeski, Ivan Riemer, Jan |
| description | The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex. |
| doi_str_mv | 10.1016/j.cmet.2015.08.019 |
| format | Article |
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Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.</description><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2015.08.019</identifier><identifier>PMID: 26387864</identifier><language>eng</language><publisher>United States</publisher><subject>Calcium - metabolism ; Calcium Channels - chemistry ; Calcium Channels - metabolism ; Calcium-Binding Proteins - antagonists & inhibitors ; Calcium-Binding Proteins - chemistry ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cation Transport Proteins - antagonists & inhibitors ; Cation Transport Proteins - chemistry ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; Dimerization ; Disulfides - chemistry ; Disulfides - metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Ions - chemistry ; Ions - metabolism ; Mitochondria - metabolism ; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors ; Mitochondrial Membrane Transport Proteins - chemistry ; Mitochondrial Membrane Transport Proteins - genetics ; Mitochondrial Membrane Transport Proteins - metabolism ; RNA Interference ; RNA, Small Interfering - metabolism</subject><ispartof>Cell metabolism, 2015-10, Vol.22 (4), p.721-733</ispartof><rights>Copyright © 2015 Elsevier Inc. 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Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.</description><subject>Calcium - metabolism</subject><subject>Calcium Channels - chemistry</subject><subject>Calcium Channels - metabolism</subject><subject>Calcium-Binding Proteins - antagonists & inhibitors</subject><subject>Calcium-Binding Proteins - chemistry</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cation Transport Proteins - antagonists & inhibitors</subject><subject>Cation Transport Proteins - chemistry</subject><subject>Cation Transport Proteins - genetics</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Dimerization</subject><subject>Disulfides - chemistry</subject><subject>Disulfides - metabolism</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Ions - chemistry</subject><subject>Ions - metabolism</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial Membrane Transport Proteins - antagonists & inhibitors</subject><subject>Mitochondrial Membrane Transport Proteins - chemistry</subject><subject>Mitochondrial Membrane Transport Proteins - genetics</subject><subject>Mitochondrial Membrane Transport Proteins - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - metabolism</subject><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kEtPwzAQhC0kREvhD3BAPhahhLWdxPERpTwqtUJCzTly7Q1NyYvYOfDvCaJcZg_zzY40hNwwCBmw5OEYmgZ9yIHFIaQhMHVG5kwJHsiIw4xcOncEEIlQ4oLMeCJSmSbRnAy7A9JML_n9XbDCHluLrafvWKN2SLuS-snfVjqCYN3a0aCl23WWs-BXOV1VDQ60HLqGbrN8yn2MtfbopojvzKFr7VDp-lRA897rT7wi56WuHV6f7oLkz0-77DXYvL2ss8dN0DOe-MACE5zFALGIUVghtJIpGL2XUsWlkjwWBlQsoTSKm1TupYWJK1M7eZxHYkGWf3_7ofsa0fmiqZzButYtdqMrmORMRCkkfEJvT-i4b9AW_VA1evgu_ncSPxd5ZHs</recordid><startdate>20151006</startdate><enddate>20151006</enddate><creator>Petrungaro, Carmelina</creator><creator>Zimmermann, Katharina M</creator><creator>Küttner, Victoria</creator><creator>Fischer, Manuel</creator><creator>Dengjel, Jörn</creator><creator>Bogeski, Ivan</creator><creator>Riemer, Jan</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20151006</creationdate><title>The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake</title><author>Petrungaro, Carmelina ; Zimmermann, Katharina M ; Küttner, Victoria ; Fischer, Manuel ; Dengjel, Jörn ; Bogeski, Ivan ; Riemer, Jan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p126t-d01321500535e3d33a9780cab7795f97253c09570fc92c87b7d0e3df8d9722243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Calcium - metabolism</topic><topic>Calcium Channels - chemistry</topic><topic>Calcium Channels - metabolism</topic><topic>Calcium-Binding Proteins - antagonists & inhibitors</topic><topic>Calcium-Binding Proteins - chemistry</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cation Transport Proteins - antagonists & inhibitors</topic><topic>Cation Transport Proteins - chemistry</topic><topic>Cation Transport Proteins - genetics</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Dimerization</topic><topic>Disulfides - chemistry</topic><topic>Disulfides - metabolism</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Ions - chemistry</topic><topic>Ions - metabolism</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial Membrane Transport Proteins - antagonists & inhibitors</topic><topic>Mitochondrial Membrane Transport Proteins - chemistry</topic><topic>Mitochondrial Membrane Transport Proteins - genetics</topic><topic>Mitochondrial Membrane Transport Proteins - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Petrungaro, Carmelina</creatorcontrib><creatorcontrib>Zimmermann, Katharina M</creatorcontrib><creatorcontrib>Küttner, Victoria</creatorcontrib><creatorcontrib>Fischer, Manuel</creatorcontrib><creatorcontrib>Dengjel, Jörn</creatorcontrib><creatorcontrib>Bogeski, Ivan</creatorcontrib><creatorcontrib>Riemer, Jan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Petrungaro, Carmelina</au><au>Zimmermann, Katharina M</au><au>Küttner, Victoria</au><au>Fischer, Manuel</au><au>Dengjel, Jörn</au><au>Bogeski, Ivan</au><au>Riemer, Jan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2015-10-06</date><risdate>2015</risdate><volume>22</volume><issue>4</issue><spage>721</spage><epage>733</epage><pages>721-733</pages><eissn>1932-7420</eissn><abstract>The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.</abstract><cop>United States</cop><pmid>26387864</pmid><doi>10.1016/j.cmet.2015.08.019</doi><tpages>13</tpages></addata></record> |
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| subjects | Calcium - metabolism Calcium Channels - chemistry Calcium Channels - metabolism Calcium-Binding Proteins - antagonists & inhibitors Calcium-Binding Proteins - chemistry Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cation Transport Proteins - antagonists & inhibitors Cation Transport Proteins - chemistry Cation Transport Proteins - genetics Cation Transport Proteins - metabolism Dimerization Disulfides - chemistry Disulfides - metabolism HEK293 Cells HeLa Cells Humans Ions - chemistry Ions - metabolism Mitochondria - metabolism Mitochondrial Membrane Transport Proteins - antagonists & inhibitors Mitochondrial Membrane Transport Proteins - chemistry Mitochondrial Membrane Transport Proteins - genetics Mitochondrial Membrane Transport Proteins - metabolism RNA Interference RNA, Small Interfering - metabolism |
| title | The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake |
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