Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization
Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechani...
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| Veröffentlicht in: | Developmental cell 2008-02, Vol.14 (2), p.193-204 |
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| creator | Cassidy-Stone, Ann Chipuk, Jerry E. Ingerman, Elena Song, Cheng Yoo, Choong Kuwana, Tomomi Kurth, Mark J. Shaw, Jared T. Hinshaw, Jenny E. Green, Douglas R. Nunnari, Jodi |
| description | Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases. |
| doi_str_mv | 10.1016/j.devcel.2007.11.019 |
| format | Article |
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Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.</description><identifier>ISSN: 1534-5807</identifier><identifier>EISSN: 1878-1551</identifier><identifier>DOI: 10.1016/j.devcel.2007.11.019</identifier><identifier>PMID: 18267088</identifier><language>eng</language><publisher>Cambridge, MA: Elsevier Inc</publisher><subject>Animals ; Apoptosis - drug effects ; bcl-2 Homologous Antagonist-Killer Protein - metabolism ; bcl-2-Associated X Protein - metabolism ; Biological and medical sciences ; Cell differentiation, maturation, development, hematopoiesis ; Cell physiology ; CELLBIO ; CELLCYCLE ; Cercopithecus aethiops ; CHEMBIO ; COS Cells ; Dynamins - antagonists & inhibitors ; Dynamins - ultrastructure ; Flow Cytometry ; Fundamental and applied biological sciences. Psychology ; HeLa Cells ; Humans ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial Membranes - drug effects ; Mitochondrial Membranes - metabolism ; Molecular and cellular biology ; Permeability - drug effects ; Quinazolinones - chemistry ; Quinazolinones - pharmacology ; Saccharomyces cerevisiae - cytology ; Saccharomyces cerevisiae - drug effects ; Structure-Activity Relationship</subject><ispartof>Developmental cell, 2008-02, Vol.14 (2), p.193-204</ispartof><rights>2008 Elsevier Inc.</rights><rights>2008 INIST-CNRS</rights><rights>2007 Elsevier Inc. All rights reserved. 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-57bf91cc48349be9ba287e5ad7a7c3b3a3b723d8e119f5410f2550328b7d0bbc3</citedby><cites>FETCH-LOGICAL-c557t-57bf91cc48349be9ba287e5ad7a7c3b3a3b723d8e119f5410f2550328b7d0bbc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1534580707004753$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20082283$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18267088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cassidy-Stone, Ann</creatorcontrib><creatorcontrib>Chipuk, Jerry E.</creatorcontrib><creatorcontrib>Ingerman, Elena</creatorcontrib><creatorcontrib>Song, Cheng</creatorcontrib><creatorcontrib>Yoo, Choong</creatorcontrib><creatorcontrib>Kuwana, Tomomi</creatorcontrib><creatorcontrib>Kurth, Mark J.</creatorcontrib><creatorcontrib>Shaw, Jared T.</creatorcontrib><creatorcontrib>Hinshaw, Jenny E.</creatorcontrib><creatorcontrib>Green, Douglas R.</creatorcontrib><creatorcontrib>Nunnari, Jodi</creatorcontrib><title>Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization</title><title>Developmental cell</title><addtitle>Dev Cell</addtitle><description>Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>bcl-2 Homologous Antagonist-Killer Protein - metabolism</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cell differentiation, maturation, development, hematopoiesis</subject><subject>Cell physiology</subject><subject>CELLBIO</subject><subject>CELLCYCLE</subject><subject>Cercopithecus aethiops</subject><subject>CHEMBIO</subject><subject>COS Cells</subject><subject>Dynamins - antagonists & inhibitors</subject><subject>Dynamins - ultrastructure</subject><subject>Flow Cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial Membranes - drug effects</subject><subject>Mitochondrial Membranes - metabolism</subject><subject>Molecular and cellular biology</subject><subject>Permeability - drug effects</subject><subject>Quinazolinones - chemistry</subject><subject>Quinazolinones - pharmacology</subject><subject>Saccharomyces cerevisiae - cytology</subject><subject>Saccharomyces cerevisiae - drug effects</subject><subject>Structure-Activity Relationship</subject><issn>1534-5807</issn><issn>1878-1551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhiMEoqXwDxDyBW5JbSeunQsS3eVjpVZFFZwt25mQWZJ4a2cj2v_Q_4xXu2qBAyePPO-88_Fk2WtGC0bZ2em6aGB20BecUlkwVlBWP8mOmZIqZ0KwpykWZZULReVR9iLGNU1lTNHn2RFT_ExSpY6z-0UHAzrTk9XYocUJ_Uh8S6YOyCVO3nV-bAKm_BJnjLvs8nY0A47kGmYwfSSrKZJr3wNJf-fm1-m5-ZkvYQNjA-P0j8nVdoJALmGwwYxAvkIYwFjs8c7sOr_MnrXJEl4d3pPs-6eP3xZf8ourz6vFh4vcCSGnXEjb1sy5SpVVbaG2hisJwjTSSFfa0pRW8rJRwFjdiorRlgtBS66sbKi1rjzJ3u99N1s7QOPSoMH0ehNwMOFWe4P678yInf7hZ83T3WrKk8G7g0HwN1uIkx4wJhh92spvo5aUK1pLmoTVXuiCjzFA-9CEUb3jqNd6z1HvOGrGdOKYyt78OeBj0QFcErw9CExM9Np0TofxQZe8FOeqfNwU0jlnhKCjQxgdNBjATbrx-P9JfgP3J8E4</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>Cassidy-Stone, Ann</creator><creator>Chipuk, Jerry E.</creator><creator>Ingerman, Elena</creator><creator>Song, Cheng</creator><creator>Yoo, Choong</creator><creator>Kuwana, Tomomi</creator><creator>Kurth, Mark J.</creator><creator>Shaw, Jared T.</creator><creator>Hinshaw, Jenny E.</creator><creator>Green, Douglas R.</creator><creator>Nunnari, Jodi</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080201</creationdate><title>Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization</title><author>Cassidy-Stone, Ann ; Chipuk, Jerry E. ; Ingerman, Elena ; Song, Cheng ; Yoo, Choong ; Kuwana, Tomomi ; Kurth, Mark J. ; Shaw, Jared T. ; Hinshaw, Jenny E. ; Green, Douglas R. ; Nunnari, Jodi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-57bf91cc48349be9ba287e5ad7a7c3b3a3b723d8e119f5410f2550328b7d0bbc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>bcl-2 Homologous Antagonist-Killer Protein - metabolism</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cell differentiation, maturation, development, hematopoiesis</topic><topic>Cell physiology</topic><topic>CELLBIO</topic><topic>CELLCYCLE</topic><topic>Cercopithecus aethiops</topic><topic>CHEMBIO</topic><topic>COS Cells</topic><topic>Dynamins - antagonists & inhibitors</topic><topic>Dynamins - ultrastructure</topic><topic>Flow Cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial Membranes - drug effects</topic><topic>Mitochondrial Membranes - metabolism</topic><topic>Molecular and cellular biology</topic><topic>Permeability - drug effects</topic><topic>Quinazolinones - chemistry</topic><topic>Quinazolinones - pharmacology</topic><topic>Saccharomyces cerevisiae - cytology</topic><topic>Saccharomyces cerevisiae - drug effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cassidy-Stone, Ann</creatorcontrib><creatorcontrib>Chipuk, Jerry E.</creatorcontrib><creatorcontrib>Ingerman, Elena</creatorcontrib><creatorcontrib>Song, Cheng</creatorcontrib><creatorcontrib>Yoo, Choong</creatorcontrib><creatorcontrib>Kuwana, Tomomi</creatorcontrib><creatorcontrib>Kurth, Mark J.</creatorcontrib><creatorcontrib>Shaw, Jared T.</creatorcontrib><creatorcontrib>Hinshaw, Jenny E.</creatorcontrib><creatorcontrib>Green, Douglas R.</creatorcontrib><creatorcontrib>Nunnari, Jodi</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Developmental cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cassidy-Stone, Ann</au><au>Chipuk, Jerry E.</au><au>Ingerman, Elena</au><au>Song, Cheng</au><au>Yoo, Choong</au><au>Kuwana, Tomomi</au><au>Kurth, Mark J.</au><au>Shaw, Jared T.</au><au>Hinshaw, Jenny E.</au><au>Green, Douglas R.</au><au>Nunnari, Jodi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization</atitle><jtitle>Developmental cell</jtitle><addtitle>Dev Cell</addtitle><date>2008-02-01</date><risdate>2008</risdate><volume>14</volume><issue>2</issue><spage>193</spage><epage>204</epage><pages>193-204</pages><issn>1534-5807</issn><eissn>1878-1551</eissn><abstract>Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.</abstract><cop>Cambridge, MA</cop><pub>Elsevier Inc</pub><pmid>18267088</pmid><doi>10.1016/j.devcel.2007.11.019</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis - drug effects bcl-2 Homologous Antagonist-Killer Protein - metabolism bcl-2-Associated X Protein - metabolism Biological and medical sciences Cell differentiation, maturation, development, hematopoiesis Cell physiology CELLBIO CELLCYCLE Cercopithecus aethiops CHEMBIO COS Cells Dynamins - antagonists & inhibitors Dynamins - ultrastructure Flow Cytometry Fundamental and applied biological sciences. Psychology HeLa Cells Humans Mitochondria - drug effects Mitochondria - metabolism Mitochondrial Membranes - drug effects Mitochondrial Membranes - metabolism Molecular and cellular biology Permeability - drug effects Quinazolinones - chemistry Quinazolinones - pharmacology Saccharomyces cerevisiae - cytology Saccharomyces cerevisiae - drug effects Structure-Activity Relationship |
| title | Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane Permeabilization |
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