The Role of FMN Loss by Mitochondrial Complex I in Neonatal Hypoxic-Ischemic Brain Injury

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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.