Role of mitochondria in apoptotic and necroptotic cell death in the developing brain.
Role of mitochondria in apoptotic and necroptotic cell death in the developing brain.
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DOI：
10.1016/j.cca.2015.01.026
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发表时间：
2015-12-07
期刊：
影响因子：
--
通讯作者：
Hagberg H
中科院分区：
文献类型：
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作者：
Thornton C;Hagberg H
缺氧缺血性脑病可导致以延迟性能量衰竭为特征的继发性脑损伤。目前，治疗性低温是婴儿严重产中窒息后唯一可用的治疗方法，它可以减少高能磷酸盐的继发性丢失，改善短期和长期结果。为了开发下一代神经保护疗法，我们迫切需要了解导致细胞死亡的潜在分子机制。缺氧缺血造成了细胞内的毒性环境，包括损伤后细胞内活性氧/亚硝酸类物质和细胞内钙的积累，导致线粒体损伤。更具体地说，线粒体呼吸受到抑制，钙信号失控。在一定的阈值下，Bax依赖的线粒体通透性会发生，从而激活caspase依赖的和凋亡诱导因子依赖的凋亡细胞死亡。此外，缺氧缺血诱导炎症，导致肿瘤坏死因子-α、TRAIL、TWINE、FasL和Toll样受体激动剂的释放，从而激活神经元和少突胶质细胞上的死亡受体。死亡受体通过caspase-8触发凋亡性死亡，通过形成坏死体(由RIP1、RIP3和MLKL组成)引发坏死性细胞死亡，两者都汇聚在线粒体上。缺氧缺血性脑病可导致以延迟性能量衰竭和兴奋性毒性为特征的继发性脑损伤。缺氧缺血引起细胞内氧自由基和细胞内钙离子的积累，导致线粒体功能障碍。线粒体损伤可导致Bax依赖的线粒体通透性，从而触发促凋亡蛋白的释放和细胞死亡。在恢复期，会产生炎症，导致死亡受体激活和坏死性下垂的诱导。
Hypoxic–ischemic encephalopathy induces secondary brain injury characterized by delayed energy failure. Currently, therapeutic hypothermia is the sole treatment available after severe intrapartum asphyxia in babies and acts to attenuate secondary loss of high energy phosphates improving both short- and long-term outcome. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. Hypoxia–ischemia creates a toxic intracellular environment including accumulation of reactive oxygen/nitrosative species and intracellular calcium after the insult, inducing mitochondrial impairment. More specifically mitochondrial respiration is suppressed and calcium signaling is dysregulated. At a certain threshold, Bax-dependent mitochondrial permeabilization will occur leading to activation of caspase-dependent and apoptosis-inducing factor-dependent apoptotic cell death. In addition, hypoxia–ischemia induces inflammation, which leads to the release of TNF-α, TRAIL, TWEAK, FasL and Toll-like receptor agonists that will activate death receptors on neurons and oligodendroglia. Death receptors trigger apoptotic death via caspase-8 and necroptotic cell death through formation of the necrosome (composed of RIP1, RIP3 and MLKL), both of which converge at the mitochondria. Hypoxic-ischemic encephalopathy induces secondary brain injury characterized by delayed energy failure and excitotoxicity. Hypoxia-ischemia triggers accumulation of reactive oxygen species andintracellular calcium, which induces mitochondrial dysfunction. Mitochondrial impairment can cause Bax-dependent mitochondrial permeabilization, which triggers release of pro-apoptotic proteins and cell death. During the recovery phase, Inflammation is produced leading to death receptor activation and induction of necroptosis.