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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Veröffentlicht in:The Journal of neuroscience 2010-02, Vol.30 (6), p.2077-2087
Hauptverfasser: 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
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container_end_page 2087
container_issue 6
container_start_page 2077
container_title The Journal of neuroscience
container_volume 30
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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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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