Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury.
Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury.
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DOI：
10.1523/jneurosci.5249-09.2010
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发表时间：
2010-02-10
期刊：
影响因子：
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通讯作者：
Starkov AA
中科院分区：
文献类型：
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作者：
Ten VS;Yao J;Ratner V;Sosunov S;Fraser DA;Botto M;Sivasankar B;Morgan BP;Silverstein S;Stark R;Polin R;Vannucci SJ;Pinsky D;Starkov AA
婴儿缺氧缺血性脑损伤是导致终生残疾的主要原因。我们报道了一种新的途径来介导缺氧缺血后的氧化性脑损伤，其中C1q起核心作用。新生小鼠由于C1q或C6缺乏或药物抑制膜攻击复合体的组装而无法激活经典或末端补体，造成缺氧缺血。只有C1q−/−小鼠表现出神经保护和减轻的氧化脑损伤。这与C1q−/−脑线粒体中活性氧物种(ROS)的产生减少和呼吸链的活性保留有关。与C1q+/+神经元相比，皮质C1q−/−神经元对缺糖耐受。然而，缺血后暴露于外源性C1q会增加线粒体ROS的产生，并增加C1q−/−神经元的死亡率。这种C1q毒性通过与抗氧化剂Trolox(6-hydroxy-2，5，7，8-tetramethylchroman-2-carboxylic酸共同暴露而被消除)。因此，补体的C1q成分，加速线粒体ROS的释放，加剧了发育中的HI脑的氧化损伤。在HI新生儿脑中，末端补体复合体被激活，但似乎是非致病的。这些发现强调了C1q介导的线粒体氧化应激比C1q沉积触发的终末补体激活在致病方面的优先地位，对于设计适当的治疗措施来治疗HI新生儿脑损伤具有重要意义。
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.