Granzyme B-induced mitochondrial ROS are required for apoptosis
Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we foun...
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| Veröffentlicht in: | Cell death and differentiation 2014-10, Vol.22 (5), p.862-874 |
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| creator | Jacquemin, G Margiotta, D Kasahara, A Bassoy, E Y Walch, M Thiery, J Lieberman, J Martinvalet, D |
| description | Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis. |
| doi_str_mv | 10.1038/cdd.2014.180 |
| format | Article |
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Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2014.180</identifier><identifier>PMID: 25361078</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/1933 ; 82/58 ; 96/2 ; 96/31 ; 96/95 ; Animals ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Cytochrome ; Dehydrogenases ; Electron Transport Complex I - genetics ; Electron Transport Complex I - metabolism ; Electron Transport Complex III - genetics ; Electron Transport Complex III - metabolism ; Granzymes - genetics ; Granzymes - metabolism ; Humans ; K562 Cells ; Kinases ; Life Sciences ; Mass spectrometry ; Metabolism ; Mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Mitochondrial DNA ; Mitochondrial Membranes - metabolism ; Original Paper ; Physiology ; Proteins ; Rats ; Reactive Oxygen Species - metabolism ; Respiration ; Scientific imaging ; Stem Cells</subject><ispartof>Cell death and differentiation, 2014-10, Vol.22 (5), p.862-874</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>Copyright Nature Publishing Group Apr 2015</rights><rights>Copyright © 2015 Macmillan Publishers Limited 2015 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-a6f1663c706c43f796d6c5c2e2ea9a3c261efa146b0c883831908520964bf3853</citedby><cites>FETCH-LOGICAL-c586t-a6f1663c706c43f796d6c5c2e2ea9a3c261efa146b0c883831908520964bf3853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392081/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392081/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41488,42557,51319,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25361078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jacquemin, G</creatorcontrib><creatorcontrib>Margiotta, D</creatorcontrib><creatorcontrib>Kasahara, A</creatorcontrib><creatorcontrib>Bassoy, E Y</creatorcontrib><creatorcontrib>Walch, M</creatorcontrib><creatorcontrib>Thiery, J</creatorcontrib><creatorcontrib>Lieberman, J</creatorcontrib><creatorcontrib>Martinvalet, D</creatorcontrib><title>Granzyme B-induced mitochondrial ROS are required for apoptosis</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). 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Consequently, GB-induced ROS significantly promote apoptosis.</description><subject>631/250/1933</subject><subject>82/58</subject><subject>96/2</subject><subject>96/31</subject><subject>96/95</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell death</subject><subject>Cytochrome</subject><subject>Dehydrogenases</subject><subject>Electron Transport Complex I - genetics</subject><subject>Electron Transport Complex I - metabolism</subject><subject>Electron Transport Complex III - genetics</subject><subject>Electron Transport Complex III - metabolism</subject><subject>Granzymes - genetics</subject><subject>Granzymes - metabolism</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Mass spectrometry</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial Membranes - metabolism</subject><subject>Original Paper</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Rats</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Respiration</subject><subject>Scientific imaging</subject><subject>Stem Cells</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkF1LwzAYhYMobk7vvJaCt3a-aT6a3ig6dAqDgR_XIUvTrWNttqQV5q83Y3NM8CqB83Dew4PQJYY-BiJudZ73E8C0jwUcoS6mKY8ZBXIc_oRBnAFNO-jM-zkA8DTjp6iTMMIxpKKL7odO1d_rykSPcVnnrTZ5VJWN1TNb565Ui-ht_B4pZyJnVm3pQlxYF6mlXTbWl_4cnRRq4c3F7u2hz-enj8FLPBoPXwcPo1gzwZtY8QJzTnQKXFNShBU510wnJjEqU0QnHJtCYconoIUgguAMBEsg43RSEMFID91te5ftpDK5NnXj1EIuXVkpt5ZWlfJvUpczObVfkpIsAYFDwfWuwNlVa3wj57Z1ddgsMU8xAGYZDdTNltLOeu9Msb-AQW50y6BbbnTLoDvgV4er9vCv3wDEW8CHqJ4ad3D1v8IfgEWJhA</recordid><startdate>20141031</startdate><enddate>20141031</enddate><creator>Jacquemin, G</creator><creator>Margiotta, D</creator><creator>Kasahara, A</creator><creator>Bassoy, E Y</creator><creator>Walch, M</creator><creator>Thiery, J</creator><creator>Lieberman, J</creator><creator>Martinvalet, D</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20141031</creationdate><title>Granzyme B-induced mitochondrial ROS are required for apoptosis</title><author>Jacquemin, G ; Margiotta, D ; Kasahara, A ; Bassoy, E Y ; Walch, M ; Thiery, J ; Lieberman, J ; Martinvalet, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c586t-a6f1663c706c43f796d6c5c2e2ea9a3c261efa146b0c883831908520964bf3853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/250/1933</topic><topic>82/58</topic><topic>96/2</topic><topic>96/31</topic><topic>96/95</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell death</topic><topic>Cytochrome</topic><topic>Dehydrogenases</topic><topic>Electron Transport Complex I - 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Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25361078</pmid><doi>10.1038/cdd.2014.180</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/250/1933 82/58 96/2 96/31 96/95 Animals Apoptosis Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Cell death Cytochrome Dehydrogenases Electron Transport Complex I - genetics Electron Transport Complex I - metabolism Electron Transport Complex III - genetics Electron Transport Complex III - metabolism Granzymes - genetics Granzymes - metabolism Humans K562 Cells Kinases Life Sciences Mass spectrometry Metabolism Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial DNA Mitochondrial Membranes - metabolism Original Paper Physiology Proteins Rats Reactive Oxygen Species - metabolism Respiration Scientific imaging Stem Cells |
| title | Granzyme B-induced mitochondrial ROS are required for apoptosis |
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