The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins
Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has be...
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| Veröffentlicht in: | The Journal of experimental medicine 1998-04, Vol.187 (8), p.1261-1271 |
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| container_title | The Journal of experimental medicine |
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| creator | Marzo, I Brenner, C Zamzami, N Susin, S A Beutner, G Brdiczka, D Rémy, R Xie, Z H Reed, J C Kroemer, G |
| description | Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family. |
| doi_str_mv | 10.1084/jem.187.8.1261 |
| format | Article |
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This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.187.8.1261</identifier><identifier>PMID: 9547337</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Apoptosis ; bcl-X Protein ; Brain - metabolism ; Cysteine Endopeptidases - metabolism ; Liposomes ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - metabolism ; Mice ; Mitochondria - metabolism ; Permeability ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Rats</subject><ispartof>The Journal of experimental medicine, 1998-04, Vol.187 (8), p.1261-1271</ispartof><rights>1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c482t-485be003ce661468e8c1cec18f4033ddc715b02937d8191def3d653d0ff0abe23</citedby><cites>FETCH-LOGICAL-c482t-485be003ce661468e8c1cec18f4033ddc715b02937d8191def3d653d0ff0abe23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9547337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marzo, I</creatorcontrib><creatorcontrib>Brenner, C</creatorcontrib><creatorcontrib>Zamzami, N</creatorcontrib><creatorcontrib>Susin, S A</creatorcontrib><creatorcontrib>Beutner, G</creatorcontrib><creatorcontrib>Brdiczka, D</creatorcontrib><creatorcontrib>Rémy, R</creatorcontrib><creatorcontrib>Xie, Z H</creatorcontrib><creatorcontrib>Reed, J C</creatorcontrib><creatorcontrib>Kroemer, G</creatorcontrib><title>The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. This is at least in part due to opening of the permeability transition (PT) pore, a multiprotein complex built up at the contact site between the inner and the outer mitochondrial membranes. The PT pore has been previously implicated in clinically relevant massive cell death induced by toxins, anoxia, reactive oxygen species, and calcium overload. Here we show that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the natural PT pore present in intact mitochondria. The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins. Although calcium, prooxidants, and several recombinant caspases (caspases 1, 2, 3, 4, and 6) enhance the permeability of PT pore-containing liposomes, recombinant Bcl-2 or Bcl-XL augment the resistance of the reconstituted PT pore complex to pore opening. Mutated Bcl-2 proteins that have lost their cytoprotective potential also lose their PT modulatory capacity. In conclusion, the PT pore complex may constitute a crossroad of apoptosis regulation by caspases and members of the Bcl-2 family.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>bcl-X Protein</subject><subject>Brain - metabolism</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Liposomes</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mitochondria - metabolism</subject><subject>Permeability</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Rats</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFr3DAQRkVJSTZpr70FdMrNrkaSbbmHQlnaphDoJT0LWRpvFGxLlbQl--_rNEtoTjnN4XvzMcMj5AOwGpiSH-9xrkF1taqBt_CGbKCRrOoboU7IhjHOK2CsOyPnOd8zBlI27Sk57RvZCdFtSLq9QxoxzWgGP_lyoCWZJfviw0JjSEhtmOOED5-oocWkHRY6hkRNDLGE7DNNuNtP5h8_HKg1OZqMmZrF0cFOFa8SrjE6GlMo6Jf8jrwdzZTx_XFekF_fvt5ur6ubn99_bL_cVFYqXiqpmgEZExbbFmSrUFmwaEGNkgnhnO2gGRjvRecU9OBwFK5thGPjyMyAXFyQz0-9cT_M6Cwu62uTjsnPJh10MF6_TBZ_p3fhj-YcOBdyLbg6FqTwe4-56Nlni9NkFgz7rLtegYBOvQpCK1mvWljB-gm0KeSccHy-Bph-1KlXnXrVqZV-1LkuXP7_wzN-9Cf-ApVYnss</recordid><startdate>19980420</startdate><enddate>19980420</enddate><creator>Marzo, I</creator><creator>Brenner, C</creator><creator>Zamzami, N</creator><creator>Susin, S A</creator><creator>Beutner, G</creator><creator>Brdiczka, D</creator><creator>Rémy, R</creator><creator>Xie, Z H</creator><creator>Reed, J C</creator><creator>Kroemer, G</creator><general>The Rockefeller University Press</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>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19980420</creationdate><title>The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins</title><author>Marzo, I ; Brenner, C ; Zamzami, N ; Susin, S A ; Beutner, G ; Brdiczka, D ; Rémy, R ; Xie, Z H ; Reed, J C ; Kroemer, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c482t-485be003ce661468e8c1cec18f4033ddc715b02937d8191def3d653d0ff0abe23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>bcl-X Protein</topic><topic>Brain - metabolism</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Liposomes</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mitochondria - metabolism</topic><topic>Permeability</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Rats</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marzo, I</creatorcontrib><creatorcontrib>Brenner, C</creatorcontrib><creatorcontrib>Zamzami, N</creatorcontrib><creatorcontrib>Susin, S A</creatorcontrib><creatorcontrib>Beutner, G</creatorcontrib><creatorcontrib>Brdiczka, D</creatorcontrib><creatorcontrib>Rémy, R</creatorcontrib><creatorcontrib>Xie, Z H</creatorcontrib><creatorcontrib>Reed, J C</creatorcontrib><creatorcontrib>Kroemer, G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marzo, I</au><au>Brenner, C</au><au>Zamzami, N</au><au>Susin, S A</au><au>Beutner, G</au><au>Brdiczka, D</au><au>Rémy, R</au><au>Xie, Z H</au><au>Reed, J C</au><au>Kroemer, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>1998-04-20</date><risdate>1998</risdate><volume>187</volume><issue>8</issue><spage>1261</spage><epage>1271</epage><pages>1261-1271</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Early in programmed cell death (apoptosis), mitochondrial membrane permeability increases. 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| fulltext | fulltext |
| identifier | ISSN: 0022-1007 |
| ispartof | The Journal of experimental medicine, 1998-04, Vol.187 (8), p.1261-1271 |
| issn | 0022-1007 1540-9538 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Apoptosis bcl-X Protein Brain - metabolism Cysteine Endopeptidases - metabolism Liposomes Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Mice Mitochondria - metabolism Permeability Proto-Oncogene Proteins c-bcl-2 - metabolism Rats |
| title | The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins |
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