The role of FMN loss by mitochondrial Complex I in neonatal hypoxic-ischemic brain injury

线粒体复合物 I 导致 FMN 丢失在新生儿缺氧缺血性脑损伤中的作用

• 批准号: 10527616
• 负责人: Alexander Galkin
• 金额: $ 44.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527616
• 关键词: Acute; Adult; Affect; Astrocytes; Attenuated; Automobile Driving; Bioenergetics; Blood; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cell Culture Techniques; Cells; Cerebral Palsy; Cessation of life; Citric Acid Cycle; Clinical Research; Complex; Consumption; Data; Development; Dissociation; Drops; Electron Transport; Encephalopathies; Energy Metabolism; Enzymes; Event; Exhibits; Failure; Flavin Mononucleotide; Flavins; Functional disorder; Generations; Glucose; Glycolysis; Health; Hour; Human; Impairment; In Vitro; Infant; Ischemia; Kinetics; Life; Measures; Membrane; Membrane Potentials; Metabolic; Metabolic Pathway; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Necrosis; Neonatal; Neurologic; Neurons; Oxidative Stress; Oxides; Oxygen; Pathway interactions; Patients; Perinatal Hypoxia; Perinatal mortality demographics; Permeability; Pharmacology; Phosphocreatine; Process; Production; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Respiration; Riboflavin; Role; Secondary to; Severities; Specificity; Stroke; Succinates; System; Temperature; Testing; Therapeutic; Time; Tissues; Work; attenuation; base; brain tissue; cell type; cofactor; cold temperature; deprivation; disability; enzyme activity; experimental study; hypoxic ischemic injury; improved outcome; in vivo; life time cost; natural hypothermia; negative affect; neonatal brain; neonatal hypoxic-ischemic brain injury; neonatal mice; neuroprotection; novel; oxidation; pre-clinical; preservation; prevent; response; stroke model

In the US, perinatal hypoxia-ischemia (HI) encephalopathy brain injury remains one of the major causes of cerebral palsy and other life-long neurological disability. The life-time cost for patients with cerebral palsy is estimated to reach 11.5 billion dollars. This dictates a need for therapeutic strategies based on better understanding the mechanisms of hypoxic ischemic injury. HI-reperfusion-associated oxidative stress negatively affects glycolysis, the Krebs cycle, mitochondrial energy metabolism, and causes abnormal permeability of the inner membrane and oxidative stress. These serve as the major factors associated with brain tissue damage in HI. However, the exact mechanisms of the so-called secondary energy failure in ischemia/reperfusion are not known. We propose that, brain oxygen deprivation leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN). Our preliminary data identifies the mechanism of flavin loss by mitochondria and show that it is taking place in the brain in vivo and can be prevented by the administration of FMN precursor, riboflavin and hypothermia. We pursue a novel hypothesis which is consistent with experimental data observed in HI and stroke models: increased ROS generation and mitochondrial bioenergetics failure. This project investigates preclinical approaches to attenuate this damage by modulating FMN handling. The data obtained in this study will significantly alter the current paradigm of the origin of neuronal ischemia/reperfusion damage. We aim to prove the major role of FMN release from mitochondria in bioenergetics failure in stroke and HI. The preclinical impact of this project is to provide a rationale for further clinical studies aimed at the reduction of post-HI brain injury.

在美国，围产期缺氧缺血（HI）脑病脑损伤仍然是导致新生儿死亡的主要原因之一。 脑瘫和其他终身神经功能障碍。脑瘫患者的终生成本为 预计将达到115亿美元。这表明需要基于更好的治疗策略 了解缺氧缺血性损伤的机制。 HI-再灌注相关的氧化应激对糖酵解、克雷布斯循环、线粒体产生负面影响 能量代谢，并导致内膜通透性异常和氧化应激。这些服务 是与 HI 脑组织损伤相关的主要因素。然而，所谓的确切机制 缺血/再灌注中的继发性能量衰竭尚不清楚。我们建议，大脑缺氧 导致线粒体复合物 I 失去其天然辅因子黄素单核苷酸 (FMN)。我们的 初步数据确定了线粒体黄素损失的机制，并表明它发生在 体内脑损伤可通过施用 FMN 前体、核黄素和低温来预防。我们追求一个新的假设，该假设与 HI 和中风模型中观察到的实验数据一致：ROS 生成增加和线粒体生物能学衰竭。该项目研究临床前 通过调节 FMN 处理来减轻这种损害的方法。本研究中获得的数据将 显着改变当前神经元缺血/再灌注损伤起源的范式。我们的目标是证明 线粒体释放 FMN 在中风和 HI 生物能学衰竭中的主要作用。临床前影响 该项目的目的是为旨在减少 HI 后脑损伤的进一步临床研究提供依据。