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

基本信息

批准号：
10378758
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378758
关键词：
Acceleration Acute Address Adenosine Triphosphate Attention Attenuated Bioenergetics Brain Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Catabolism Cells 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 Neuraxis Neurologic Dysfunctions Neurons Nicotinamide adenine dinucleotide Nitric Oxide Outcome Oxidative Phosphorylation Oxides Oxidoreductase Oxygen Pathway interactions Pharmacology Play Production Quinones Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Resistance Respiration Role Severities Speed Sulfides Therapeutic Thiosulfate Sulfurtransferase base brain cell cell injury clinical practice complex IV deprivation improved inhibitor knock-down male mortality neuronal survival neurotoxicity normoxia overexpression oxidation preconditioning preservation prevent response

项目摘要

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完整性。尽管缺血性脑损伤是发病率和死亡率的主要原因死亡率，导致大脑缺血引起的能量衰竭的机制不完全明白了。硫化氢是一种环境危害，因其神经毒性而闻名。在哺乳动物细胞中，H2S 由转硫途径产生，并在线粒体中被硫化物氧化酶氧化包括硫化醌氧化还原酶（SQR）。当氧气充足时，硫化物氧化电子到达线粒体电子传递链（ETC），从而促进三磷酸腺苷（ATP）合成。相反，缺氧会刺激硫化物合成并阻碍硫化物氧化，从而导致硫化物积累。缺血期间累积的硫化物抑制ETC复合体IV并加重再灌注受伤。因此，硫化物分解代谢可能在缺氧期间的能量稳态中发挥关键作用和再氧合时的细胞损伤。然而，硫化物分解代谢对大脑生物能的作用迄今为止，急性缺氧期间很少引起关注。 SQR 通常表示为非常低中枢神经系统中的水平，解释了大脑中硫化物消耗速度特别慢的原因。在初步研究中，我们观察到雌性小鼠大脑中的 SQR 水平较高，并且比雄性小鼠更能抵抗缺氧，而敲低大脑 SQR 则增加了雌性小鼠的敏感性使小鼠缺氧。小鼠大脑中 SQR 过度表达可预防神经功能障碍和死亡全脑缺血和再灌注（I/R）。药理学硫化物清除剂可预防 ETC 功能障碍并改善了在缺氧条件下培养的人类细胞或遭受缺氧的小鼠大脑中的能量产生脑缺血。基于这些观察，我们假设防止硫化物在通过增强硫化物氧化或药物硫化物清除剂来预防 ETC 功能障碍在缺氧期间并减轻大脑缺血/再灌注损伤。为了解决这个假设，我们建议：为了确定增强的硫化物氧化对缺血性脑损伤严重程度的影响（目标1），表征内源性硫化物分解代谢在线粒体功能和响应中的作用缺血性脑损伤（目标 2），并确定硫化物氧化的神经保护作用机制以及脑缺血再灌注后硫化物清除的治疗潜力。（目标 3）。预计拟议的研究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缺血性脑损伤中的分解代谢。