Mitochondrial complex-I as a target for metabolic resuscitation in perinatal hypoxic-ischemic brain injury

总结 全世界每年因围产期缺氧缺血性损伤而死亡的人数达到120万。在美国， 围产期HI脑损伤仍然是脑性瘫痪（CP）和终身神经系统疾病的主要原因之一， 残疾。据估计，CP患者的终身费用达到115亿美元。这就要求 需要更好地了解HI损伤机制的基础上的治疗策略。我们建议， 在再灌注时，用新化合物MitoSNO抑制复合物-I恢复保护发育中的脑 抗HI损伤。MitoSNO是一种靶向药物，通过S- Cys-39残基的亚硝化。因为，C-I的重新激活支持了反向电子传递 ROS产生的机制，提出的神经保护机制是再灌注的衰减， 引发氧化应激和保护D-型免于硫醇的不可逆氧化。目标1确定a 琥珀酸依赖性线粒体呼吸对加速ROS生成和 由再灌注启动的生物能量学恢复。从机制上讲，这一目标为抑制提供了理论基础 复合物-I恢复阻断反向电子传递，ROS产生的机制， 再灌注目的1和2确定MitoSNO对C-I恢复的瞬时抑制是否减弱 线粒体氧化损伤并保持线粒体对Ca++诱导的mPTP发展的耐受性， 以及这是否限制了二次能源故障的严重性。目的2解决MitoSNO的特异性 对C-I的D-形式的Cys 39的S-亚硝化的神经保护作用。目标2还评估了长期 MitoSNO的神经保护作用。这个项目为我们提供了一个强大的机械背景， 开发临床相关的新型代谢复苏治疗策略， 代谢恢复是主流原则。

SUMMARY A worldwide mortality from perinatal hypoxic-ischemic insult reaches 1.2 million annually. In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy (CP) and life-long neurological disability. The life-time cost for patients with CP was estimated to reach 11.5 billion dollars. This dictates a need for therapeutic strategies based on better understanding the mechanisms of HI injury. We propose that, upon reperfusion, inhibition of complex-I recovery with novel compound, MitoSNO, protects developing brain against HI injury. MitoSNO is mitochondria-targeted agent that maintains C-I in the de-active form (D) via S- nitrosation of Cys-39 residue. Because, the reactivation of the C-I supports a reverse-electron transport mechanism of ROS production, the proposed mechanism of neuroprotection is attenuation of the reperfusion- initiated oxidative stress and protection of the D-form from irreversible oxidation of thiols. Aim 1 determines a contribution of succinate-dependent mitochondrial respiration to accelerated ROS generation and to bioenergetics recovery initiated by the reperfusion. Mechanistically, this aim provides the rationale for inhibition of complex-I recovery to block reverse electron transport, the mechanism for ROS generation burst in reperfusion. Aim 1 and 2 determines whether transient inhibition of C-I recovery with MitoSNO attenuates mitochondrial oxidative damage and preserves mitochondrial tolerance to Ca++ induced development of mPTP, and whether this limits the severity of secondary energy failure. Aim 2 addresses specificity of MitoSNO neuroprotective action to the S-nitrosation the Cys39 in the D-form of the C-I. Aim 2 also evaluates long-term neuroprotective effects of the MitoSNO. This project offers a strong mechanistic background for the development of clinically relevant and novel therapeutic strategy of metabolic resuscitation in which gradual metabolic recovery is the mainstream principle.