Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury
Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 de...
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creator | Ten, Vadim S Yao, Jun Ratner, Veniamin Sosunov, Sergey Fraser, Deborah A Botto, Marina Sivasankar, Baalasubramanian Morgan, B. Paul Silverstein, Samuel Stark, Raymond Polin, Richard Vannucci, Susan J Pinsky, David Starkov, Anatoly A |
description | Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation. |
doi_str_mv | 10.1523/JNEUROSCI.5249-09.2010 |
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Paul ; Silverstein, Samuel ; Stark, Raymond ; Polin, Richard ; Vannucci, Susan J ; Pinsky, David ; Starkov, Anatoly A</creator><creatorcontrib>Ten, Vadim S ; Yao, Jun ; Ratner, Veniamin ; Sosunov, Sergey ; Fraser, Deborah A ; Botto, Marina ; Sivasankar, Baalasubramanian ; Morgan, B. Paul ; Silverstein, Samuel ; Stark, Raymond ; Polin, Richard ; Vannucci, Susan J ; Pinsky, David ; Starkov, Anatoly A</creatorcontrib><description>Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.5249-09.2010</identifier><identifier>PMID: 20147536</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>Animals ; Animals, Newborn ; Brain Infarction - metabolism ; Brain Infarction - pathology ; CD59 Antigens - pharmacology ; Cells, Cultured ; Complement Activation ; Complement C1q - genetics ; Complement C1q - physiology ; Cytosol - metabolism ; Female ; Glucose - deficiency ; Hypoxia-Ischemia, Brain - metabolism ; Hypoxia-Ischemia, Brain - pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria - physiology ; Neurons - metabolism ; Oxidative Stress ; Oxygen - metabolism ; Reactive Oxygen Species - metabolism</subject><ispartof>The Journal of neuroscience, 2010-02, Vol.30 (6), p.2077-2087</ispartof><rights>Copyright © 2010 the authors 0270-6474/10/302077-11$15.00/0 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-7ed8cea8141470550def660a81063e2e175bdff76bee2be31ba4fe80cebd868f3</citedby><cites>FETCH-LOGICAL-c563t-7ed8cea8141470550def660a81063e2e175bdff76bee2be31ba4fe80cebd868f3</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/PMC2821109/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821109/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20147536$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ten, Vadim S</creatorcontrib><creatorcontrib>Yao, Jun</creatorcontrib><creatorcontrib>Ratner, Veniamin</creatorcontrib><creatorcontrib>Sosunov, Sergey</creatorcontrib><creatorcontrib>Fraser, Deborah A</creatorcontrib><creatorcontrib>Botto, Marina</creatorcontrib><creatorcontrib>Sivasankar, Baalasubramanian</creatorcontrib><creatorcontrib>Morgan, B. Paul</creatorcontrib><creatorcontrib>Silverstein, Samuel</creatorcontrib><creatorcontrib>Stark, Raymond</creatorcontrib><creatorcontrib>Polin, Richard</creatorcontrib><creatorcontrib>Vannucci, Susan J</creatorcontrib><creatorcontrib>Pinsky, David</creatorcontrib><creatorcontrib>Starkov, Anatoly A</creatorcontrib><title>Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Brain Infarction - metabolism</subject><subject>Brain Infarction - pathology</subject><subject>CD59 Antigens - pharmacology</subject><subject>Cells, Cultured</subject><subject>Complement Activation</subject><subject>Complement C1q - genetics</subject><subject>Complement C1q - physiology</subject><subject>Cytosol - metabolism</subject><subject>Female</subject><subject>Glucose - deficiency</subject><subject>Hypoxia-Ischemia, Brain - metabolism</subject><subject>Hypoxia-Ischemia, Brain - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mitochondria - physiology</subject><subject>Neurons - metabolism</subject><subject>Oxidative Stress</subject><subject>Oxygen - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkVFv0zAUhS0EYmXwF6Y8wVPKdZzYyQsSlMGKtlVi7NlynJvFU2Jndrqu_x6HjgqefOT73eNjHULOKCxpkbGPP67Pb39ublbrZZHlVQrVMgMKL8giTqs0y4G-JAvIBKQ8F_kJeRPCPQAIoOI1OYlsLgrGF2RcuWHscUA7JbN09o-iD8kVNkZNGJIrMzndOdt4o9Kv3jyiTTZPplFTlMnN5DGExNjkGp1Vk-qTi_3onoxO10F3OBidfPEqztf2fuv3b8mrVvUB3z2fp-T22_mv1UV6ufm-Xn2-THXB2ZQKbEqNqqR5TApFAQ22nEO8AM4wQyqKumlbwWvErEZGa5W3WILGuil52bJT8ungO27rARsdv-VVL0dvBuX30ikj_59Y08k79yizMqMUqmjw4dnAu4cthkkOJmjse2XRbYMUjHER480kP5DauxA8tsdXKMi5LXlsS85tSajk3FZcPPs343Htbz0ReH8AOnPX7YxHGQbV9xGncrfbMZA8wkKw3-sbolk</recordid><startdate>20100210</startdate><enddate>20100210</enddate><creator>Ten, Vadim S</creator><creator>Yao, Jun</creator><creator>Ratner, Veniamin</creator><creator>Sosunov, Sergey</creator><creator>Fraser, Deborah A</creator><creator>Botto, Marina</creator><creator>Sivasankar, Baalasubramanian</creator><creator>Morgan, B. Paul</creator><creator>Silverstein, Samuel</creator><creator>Stark, Raymond</creator><creator>Polin, Richard</creator><creator>Vannucci, Susan J</creator><creator>Pinsky, David</creator><creator>Starkov, Anatoly A</creator><general>Soc Neuroscience</general><general>Society for Neuroscience</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100210</creationdate><title>Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury</title><author>Ten, Vadim S ; Yao, Jun ; Ratner, Veniamin ; Sosunov, Sergey ; Fraser, Deborah A ; Botto, Marina ; Sivasankar, Baalasubramanian ; Morgan, B. 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Paul</creatorcontrib><creatorcontrib>Silverstein, Samuel</creatorcontrib><creatorcontrib>Stark, Raymond</creatorcontrib><creatorcontrib>Polin, Richard</creatorcontrib><creatorcontrib>Vannucci, Susan J</creatorcontrib><creatorcontrib>Pinsky, David</creatorcontrib><creatorcontrib>Starkov, Anatoly A</creatorcontrib><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>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ten, Vadim S</au><au>Yao, Jun</au><au>Ratner, Veniamin</au><au>Sosunov, Sergey</au><au>Fraser, Deborah A</au><au>Botto, Marina</au><au>Sivasankar, Baalasubramanian</au><au>Morgan, B. Paul</au><au>Silverstein, Samuel</au><au>Stark, Raymond</au><au>Polin, Richard</au><au>Vannucci, Susan J</au><au>Pinsky, David</au><au>Starkov, Anatoly A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2010-02-10</date><risdate>2010</risdate><volume>30</volume><issue>6</issue><spage>2077</spage><epage>2087</epage><pages>2077-2087</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.</abstract><cop>United States</cop><pub>Soc Neuroscience</pub><pmid>20147536</pmid><doi>10.1523/JNEUROSCI.5249-09.2010</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Animals, Newborn Brain Infarction - metabolism Brain Infarction - pathology CD59 Antigens - pharmacology Cells, Cultured Complement Activation Complement C1q - genetics Complement C1q - physiology Cytosol - metabolism Female Glucose - deficiency Hypoxia-Ischemia, Brain - metabolism Hypoxia-Ischemia, Brain - pathology Mice Mice, Inbred C57BL Mice, Knockout Mitochondria - physiology Neurons - metabolism Oxidative Stress Oxygen - metabolism Reactive Oxygen Species - metabolism |
title | Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury |
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