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

在美国，围产期缺氧缺血(HI)脑病脑损伤仍然是导致 脑性瘫痪和其他终生神经残疾。脑性瘫痪患者的终生成本是 估计达到115亿美元。这就要求基于更好的治疗策略的需要 了解缺氧缺血性损伤的机制。缺氧再灌注相关的氧化应激对糖酵解、Krebs循环、线粒体 能量代谢，并导致内膜通透性异常和氧化应激。这些服务 作为脑缺血后脑组织损伤的主要相关因素。然而，所谓的 脑缺血/再灌流中继发性能量衰竭尚不清楚。我们认为，大脑缺氧 导致线粒体复合体I失去其天然辅因子黄素单核苷酸(FMN)。我们的 初步数据确定了黄素通过线粒体丢失的机制，并表明它发生在 FMN前体、核黄素和亚低温可预防。我们追求一个新的假说，这与在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量学失效。这个项目调查的是临床前 通过调整FMN处理来减轻这种损害的方法。这项研究中获得的数据将 显著改变了目前关于神经元缺血/再灌注损伤起源的范式。我们的目标是证明 FMN从线粒体释放在卒中和HI的生物能量学失败中的主要作用。临床前的影响 这一项目的目的是为进一步的临床研究提供理论基础，旨在减少HI后的脑损伤。

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.