Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain
Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption...
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| Veröffentlicht in: | Cell 2004-06, Vol.117 (6), p.773-786 |
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| container_title | Cell |
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| creator | Ricci, Jean-Ehrland Muñoz-Pinedo, Cristina Fitzgerald, Patrick Bailly-Maitre, Béatrice Perkins, Guy A Yadava, Nagendra Scheffler, Immo E Ellisman, Mark H Green, Douglas R |
| description | Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (ΔΨm), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain ΔΨm and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis. |
| doi_str_mv | 10.1016/j.cell.2004.05.008 |
| format | Article |
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Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Amino Acid Sequence - physiology</subject><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Caspases - metabolism</subject><subject>Catalytic Domain - genetics</subject><subject>Electron Transport Chain Complex Proteins - metabolism</subject><subject>Electron Transport Complex I - genetics</subject><subject>Electron Transport Complex I - metabolism</subject><subject>Energy Metabolism - genetics</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Intracellular Membranes - metabolism</subject><subject>Intracellular Membranes - ultrastructure</subject><subject>Mice</subject><subject>Microscopy, Electron</subject><subject>Mitochondria - enzymology</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - ultrastructure</subject><subject>Molecular Sequence Data</subject><subject>Mutation - genetics</subject><subject>NADH Dehydrogenase - genetics</subject><subject>NADH Dehydrogenase - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhS0EokvhD3BAPnFLamfjOJa4VGkLK7Xqoe3ZcuxJ16usHWynoj-E_4vT3YobnEaa-d4b6T2EPlNSUkKbs12pYRzLipC6JKwkpH2DVpQIXtSUV2_RihBRFW3D6xP0IcYdyQRj7D06oYzmNW9X6PeFjWGekvUO-wHf2OT11jsTrBrx1ez0y8XMwbpHfD75KfloI95EfAPGqgQG98-4U3FSEXA3gnpSj7BYpS3giTN8N_ezs2lZdX4_jfALb17vlyPoFPKD-6BcnHxIuNsq6z6id4MaI3w6zlP0cHV53_0orm-_b7rz60LXYp0KJkTfayqM4SCEUmxouGpVOwy87llGqqFVALymFfC-aQlv2KBNzRgfKGnb9Sn6evCdgv85Q0xyb-MSqnLg5yh5zpbRNf8vSLkQLLtnsDqAOvgYAwxyCnavwrOkRC6tyZ1cdHJpTRImcydZ9OXoPvd7MH8lx5oy8O0AQA7jyUKQUVtwOlcQcoLSePsv_z_FrKoc</recordid><startdate>20040611</startdate><enddate>20040611</enddate><creator>Ricci, Jean-Ehrland</creator><creator>Muñoz-Pinedo, Cristina</creator><creator>Fitzgerald, Patrick</creator><creator>Bailly-Maitre, Béatrice</creator><creator>Perkins, Guy A</creator><creator>Yadava, Nagendra</creator><creator>Scheffler, Immo E</creator><creator>Ellisman, Mark H</creator><creator>Green, Douglas R</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7TM</scope><scope>7X8</scope></search><sort><creationdate>20040611</creationdate><title>Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain</title><author>Ricci, Jean-Ehrland ; Muñoz-Pinedo, Cristina ; Fitzgerald, Patrick ; Bailly-Maitre, Béatrice ; Perkins, Guy A ; Yadava, Nagendra ; Scheffler, Immo E ; Ellisman, Mark H ; Green, Douglas R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-599bbc19dd7e99aa5f67a8a8ff74b54932f8aee7412e7b680765fcd4557f10883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Amino Acid Sequence - physiology</topic><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Caspases - metabolism</topic><topic>Catalytic Domain - genetics</topic><topic>Electron Transport Chain Complex Proteins - metabolism</topic><topic>Electron Transport Complex I - genetics</topic><topic>Electron Transport Complex I - metabolism</topic><topic>Energy Metabolism - genetics</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Intracellular Membranes - metabolism</topic><topic>Intracellular Membranes - ultrastructure</topic><topic>Mice</topic><topic>Microscopy, Electron</topic><topic>Mitochondria - enzymology</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - ultrastructure</topic><topic>Molecular Sequence Data</topic><topic>Mutation - genetics</topic><topic>NADH Dehydrogenase - genetics</topic><topic>NADH Dehydrogenase - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ricci, Jean-Ehrland</creatorcontrib><creatorcontrib>Muñoz-Pinedo, Cristina</creatorcontrib><creatorcontrib>Fitzgerald, Patrick</creatorcontrib><creatorcontrib>Bailly-Maitre, Béatrice</creatorcontrib><creatorcontrib>Perkins, Guy A</creatorcontrib><creatorcontrib>Yadava, Nagendra</creatorcontrib><creatorcontrib>Scheffler, Immo E</creatorcontrib><creatorcontrib>Ellisman, Mark H</creatorcontrib><creatorcontrib>Green, Douglas R</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ricci, Jean-Ehrland</au><au>Muñoz-Pinedo, Cristina</au><au>Fitzgerald, Patrick</au><au>Bailly-Maitre, Béatrice</au><au>Perkins, Guy A</au><au>Yadava, Nagendra</au><au>Scheffler, Immo E</au><au>Ellisman, Mark H</au><au>Green, Douglas R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2004-06-11</date><risdate>2004</risdate><volume>117</volume><issue>6</issue><spage>773</spage><epage>786</epage><pages>773-786</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (ΔΨm), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain ΔΨm and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. 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| subjects | Adenosine Triphosphate - metabolism Amino Acid Sequence - physiology Animals Apoptosis - physiology Caspases - metabolism Catalytic Domain - genetics Electron Transport Chain Complex Proteins - metabolism Electron Transport Complex I - genetics Electron Transport Complex I - metabolism Energy Metabolism - genetics HeLa Cells Humans Intracellular Membranes - metabolism Intracellular Membranes - ultrastructure Mice Microscopy, Electron Mitochondria - enzymology Mitochondria - genetics Mitochondria - ultrastructure Molecular Sequence Data Mutation - genetics NADH Dehydrogenase - genetics NADH Dehydrogenase - metabolism Reactive Oxygen Species - metabolism |
| title | Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain |
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