Mitochondrial complex-I as a target for metabolic resuscitation in perinatal hypoxic-ischemic brain injury

SUMMARY A worldwide mortality from perinatal hypoxic-ischemic insult reaches 1.2 million annually. In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy (CP) and life-long neurological disability. The life-time cost for patients with CP was estimated to reach 11.5 billion dollars. This dictates a need for therapeutic strategies based on better understanding the mechanisms of HI injury. We propose that, upon reperfusion, inhibition of complex-I recovery with novel compound, MitoSNO, protects developing brain against HI injury. MitoSNO is mitochondria-targeted agent that maintains C-I in the de-active form (D) via S- nitrosation of Cys-39 residue. Because, the reactivation of the C-I supports a reverse-electron transport mechanism of ROS production, the proposed mechanism of neuroprotection is attenuation of the reperfusion- initiated oxidative stress and protection of the D-form from irreversible oxidation of thiols. Aim 1 determines a contribution of succinate-dependent mitochondrial respiration to accelerated ROS generation and to bioenergetics recovery initiated by the reperfusion. Mechanistically, this aim provides the rationale for inhibition of complex-I recovery to block reverse electron transport, the mechanism for ROS generation burst in reperfusion. Aim 1 and 2 determines whether transient inhibition of C-I recovery with MitoSNO attenuates mitochondrial oxidative damage and preserves mitochondrial tolerance to Ca++ induced development of mPTP, and whether this limits the severity of secondary energy failure. Aim 2 addresses specificity of MitoSNO neuroprotective action to the S-nitrosation the Cys39 in the D-form of the C-I. Aim 2 also evaluates long-term neuroprotective effects of the MitoSNO. This project offers a strong mechanistic background for the development of clinically relevant and novel therapeutic strategy of metabolic resuscitation in which gradual metabolic recovery is the mainstream principle.