Role of sulfide catabolism in ischemic brain injury

硫化物分解代谢在缺血性脑损伤中的作用

• 批准号: 10588192
• 负责人: FUMITO ICHINOSE
• 金额: $ 34.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588192
• 关键词: Acceleration; Acute; Address; Adenosine Triphosphate; Attention; Attenuated; Bioenergetics; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Ischemia; Catabolism; Cells; Central Nervous System; Cerebral Ischemia; Cerebrum; Cessation of life; Complex; Consumption; Dependovirus; Electron Transport; Electrons; Encephalopathies; Environmental Hazards; Enzymes; Failure; Female; Functional disorder; Histologic; Homeostasis; Human; Hydrogen Sulfide; Hypoxia; Impairment; Incubated; Inhalation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Mammalian Cell; Mediating; Metabolism; Methods; Mitochondria; Morbidity - disease rate; Mus; NADH; Neurologic Dysfunctions; Neurons; Nicotinamide adenine dinucleotide; Nitric Oxide; Outcome; Oxidative Phosphorylation; Oxidoreductase; Oxygen; Pathway interactions; Play; Production; Quinones; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Resistance; Respiration; Role; Severities; Speed; Sulfides; Therapeutic; Thiosulfate Sulfurtransferase; brain cell; cell injury; cerebral ischemic injury; clinical practice; complex IV; deprivation; improved; inhibitor; ischemic injury; knock-down; male; mortality; neuronal survival; neuroprotection; neurotoxicity; normoxia; overexpression; oxidation; pharmacologic; preconditioning; preservation; prevent; response

The brain is exquisitely sensitive to the lack of oxygen. Acute oxygen deprivation inhibits mitochondrial energy production impairing the cellular integrity. Although ischemic brain injury is a leading cause of morbidity and mortality, mechanism responsible for the ischemia-induced energy failure of the brain is incompletely understood. Hydrogen sulfide is an environmental hazard well known for its neurotoxicity. In mammalian cells, H2S is produced by the transsulfuration pathway and is oxidized in mitochondria by sulfide oxidation enzymes including sulfide quinone oxidoreductase (SQR). When oxygen is abundant, sulfide oxidation donates electrons to the mitochondrial electron transport chain (ETC), thereby promoting adenosine triphosphate (ATP) synthesis. In contrast, oxygen deprivation stimulates sulfide synthesis and hinders sulfide oxidation, leading to sulfide accumulation. Accumulated sulfide inhibits ETC complex IV during ischemia and aggravate reperfusion injury. Therefore, sulfide catabolism may play a pivotal role in the energy homeostasis during oxygen shortage and cellular injury upon reoxygenation. However, role of sulfide catabolism on the bioenergetics of the brain during acute oxygen deprivation has thus far attracted little attention. SQR is normally expressed at very low levels in the central nervous system, explaining the particularly slow rate of sulfide consumption in the brain. In preliminary studies, we observed that female mice had higher levels of SQR in the brain and were more resistant to hypoxia than male mice, whereas, knockdown of brain SQR increased the sensitivity of female mice to hypoxia. SQR overexpression in the brain of mice prevented neurologic dysfunction and death after global cerebral ischemia and reperfusion (I/R). Pharmacological sulfide scavengers prevented ETC dysfunction and improved energy production in human cells incubated in hypoxia or in the brains of mice subjected to cerebral ischemia. Based on these observations, we hypothesize that preventing sulfide accumulation in the brain either by enhanced sulfide oxidation or pharmacologic sulfide scavenger prevents ETC dysfunction during oxygen shortage and attenuates ischemia/reperfusion injury of the brain. To address this hypothesis, we propose: To determine the effects of enhanced sulfide oxidation on the severity of ischemic brain injury (Aim1), to characterize the role of endogenous sulfide catabolism in the mitochondrial function and response to ischemic brain injury (Aim 2), and to define the mechanism of the neuroprotective effects of sulfide oxidation and therapeutic potential of sulfide scavenging after cerebral I/R. (Aim 3). Proposed studies are anticipated to illuminate the critical role of sulfide in mitochondrial respiration and uncover a therapeutic potential of sulfide catabolism in ischemic brain injury.

大脑对缺氧非常敏感。急性缺氧抑制线粒体能量 生产损害细胞的完整性。虽然缺血性脑损伤是发病的主要原因， 死亡率，负责缺血诱导的脑能量衰竭的机制不完全 明白 硫化氢是一种以神经毒性而闻名的环境危害。在哺乳动物细胞中， 通过转硫途径产生，并在线粒体中被硫化物氧化酶氧化 包括硫化物醌氧化还原酶（SQR）。当氧气充足时， 线粒体电子传递链（ETC），从而促进三磷酸腺苷（ATP） 合成.相反，缺氧刺激硫化物合成并阻碍硫化物氧化，导致 硫化物积累硫化物蓄积抑制缺血时ETC复合物IV并加重再灌注 损伤因此，硫化物催化剂可能在缺氧时的能量平衡中起着关键作用 和细胞损伤。然而，硫化物催化剂对大脑生物能量学的作用 在急性缺氧期间，迄今为止很少引起注意。SQR通常表示为非常低 硫化物在中枢神经系统中的水平，解释了大脑中硫化物消耗的速度特别慢。 在初步研究中，我们观察到雌性小鼠大脑中SQR水平较高， 脑SQR基因敲低可增加雌性小鼠对缺氧的敏感性， 小鼠缺氧。SQR在小鼠脑中的过表达防止了神经功能障碍和死亡， 全脑缺血再灌注（I/R）。药理学硫化物清除剂预防ETC功能障碍 以及在缺氧环境中培养的人类细胞或在经历缺氧的小鼠大脑中提高能量产生。 脑缺血根据这些观察，我们假设，防止硫化物积累在 通过增强硫化物氧化或药理学硫化物清除剂预防ETC功能障碍 并减轻脑缺血/再灌注损伤。为了解决这个问题，我们 目的：确定增强的硫化物氧化对缺血性脑损伤（Aim 1）严重程度的影响， 表征内源性硫化物催化剂在线粒体功能和对 缺血性脑损伤（目的2），并确定硫化物氧化的神经保护作用的机制 和脑I/R后硫化物清除的治疗潜力。(Aim（3）第三章。预计拟议的研究将 阐明硫化物在线粒体呼吸中的关键作用，并揭示硫化物的治疗潜力 在缺血性脑损伤中的作用