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

线粒体复合物-I 作为围产期缺氧缺血性脑损伤代谢复苏的靶点

• 批准号: 9893935
• 负责人: Vadim S Ten
• 金额: $ 39.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893935
• 关键词: Address; Affect; Attenuated; Bioenergetics; Blood Circulation; Brain; Cerebral Palsy; Child; Complex; Data; Development; Electron Transport; Failure; Functional disorder; Generations; Hypoxia; Hypoxic-Ischemic Brain Injury; Life; Link; Mainstreaming; Metabolic; Mitochondria; Mitochondrial Matrix; Modification; Molecular Conformation; Neurologic; Neurologic Deficit; Neurological outcome; Nitrosation; Oxidative Phosphorylation; Oxidative Stress; Oxides; Pathogenicity; Pathway interactions; Patients; Perinatal Hypoxia; Perinatal mortality demographics; Pharmacology; Play; Prevention; Production; Proton-Motive Force; Reactive Oxygen Species; Recovery; Regimen; Reperfusion Injury; Reperfusion Therapy; Respiration; Resuscitation; Role; S-Nitrosothiols; SKIL gene; Secondary to; Severities; Site; Source; Specificity; Succinates; Sulfhydryl Compounds; Testing; Therapeutic; Time; attenuation; base; clinical development; clinically relevant; disability; hypoxia neonatorum; innovation; ischemic injury; life time cost; mitochondrial dysfunction; mitochondrial membrane; mitochondrial metabolism; mitochondrial permeability transition pore; neuroprotection; novel; novel therapeutics; oxidation; oxidative damage; preservation; prevent; response; success; targeted agent

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.

摘要 全球每年因围产期缺氧缺血性损伤而死亡的人数高达120万。在美国， 围产期缺氧脑损伤仍然是脑性瘫痪(CP)和终生神经损伤的主要原因之一 残疾。据估计，慢性阻塞性肺病患者的生命成本高达115亿美元。这规定了一个 需要在更好地了解HI损伤机制的基础上制定治疗策略。我们建议， 在再灌流后，用新化合物MitoSNO抑制Complex-I恢复保护发育中的大脑 对抗HI损伤。MitoSNO是一种线粒体靶向制剂，通过S维持C-I的去活性形式(D)。 Cys-39残基的亚硝化。因为，C-I的重新激活支持反向电子传输 ROS的产生机制，提出的神经保护机制是减弱再灌流- 引发氧化应激并保护D-型免受硫醇不可逆氧化的影响。目标1确定一个 依赖琥珀酸的线粒体呼吸对加速ROS生成的贡献 再灌流引发的生物能量学恢复。从机制上讲，这一目标提供了抑制的理由。 通过恢复络合物-I来阻断反向电子传递，ROS的产生机制突然爆发 再灌流。目标1和目标2确定MitoSNO对C-I恢复的短暂抑制是否减弱 线粒体氧化损伤并保护线粒体对钙离子诱导的MPTP发育的耐受性 以及这是否限制了二次能源故障的严重性。目标2解决MitoSNO的特殊性 C-I的D-型半胱氨酸-39 S亚硝化的神经保护作用AIM 2还评估长期 MitoSNO的神经保护作用。这个项目提供了一个强大的机械背景 循序渐进的代谢复苏临床相关新治疗策略的发展 新陈代谢恢复是主流原则。