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

在美国，围产期缺氧缺血性（HI）脑病脑损伤仍然是主要原因之一， 脑瘫和其他终身神经系统残疾。脑瘫患者的生活成本是 预计将达到115亿美元。这就要求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、Krebs循环、线粒体膜电位和线粒体膜电位的影响 能量代谢，并导致内膜的异常渗透性和氧化应激。这些用于 是HI脑组织损伤的主要相关因素。然而，所谓的“ 局部缺血/再灌注中的二次能量衰竭是未知的。我们认为大脑缺氧 导致线粒体复合物I失去其天然辅因子黄素单核苷酸（FMN）的状况。我们 初步数据确定了线粒体损失黄素的机制，并表明这是在线粒体中发生的。 脑内的FMN前体，核黄素和低温的管理，可以防止。我们追求一种新的假设，这是一致的实验数据中观察到的HI和中风模型：增加ROS的产生和线粒体生物能量学失败。本项目研究临床前 通过调节FMN处理来减弱这种损害的方法。本研究中获得的数据将 显著改变了神经元缺血/再灌注损伤起源的现有范例。我们的目标是证明 线粒体释放FMN在中风和HI的生物能量学失效中的主要作用。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理论基础。

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.