Mitochondrial dysfunction is the most fundamental mechanism of cell damage in cerebral hypoxia-ischemia and reperfusion. Mitochondrial respiratory chain (MRC) is increasingly recognized as a source for reactive oxygen species (ROS) in the postischemic tissue. Potentially, ROS originating in MRC can contribute to the reperfusion-driven oxidative stress, promoting mitochondrial membrane permeabilization. The loss of mitochondrial membranes integrity during reperfusion is considered as the major mechanism of secondary energy failure. This paper focuses on current data that support a pathogenic role of ROS originating from mitochondrial respiratory chain in the promotion of secondary energy failure and proposes potential therapeutic strategy against reperfusion-driven oxidative stress following hypoxia-ischemia-reperfusion injury of the developing brain. 1. Introduction Perinatal hypoxic-ischemic (HI) brain injury is one of the most common causes of severe neurological handicap in children. Estimated life-time costs to support children with cerebral palsy, a common outcome of HI brain injury in neonates, reached 11.5 billion dollars in 2003 [1]. Unfortunately, our understanding the mechanisms of the HI brain injury is not deep enough for the development of mechanism-targeted therapeutic interventions in this disease. Even therapeutic mechanisms of post-HI cerebral hypothermia (the only clinically proven neuroprotective strategy) are still not well defined which precludes an optimal use of this potentially powerful strategy. Physiologically, HI brain injury could be defined as an acute oxygen and nutrients deprivation to the brain caused by a collapse of cerebral circulation. Hypoxia-ischemia results in severe cellular bioenergetics failure, and if cerebral circulation is not restored, then the brain death is unpreventable. However, if the cerebral circulation is restored for example, as a result of successful resuscitation, then cerebral reperfusion ensures with a full or partial brain recovery. Unfortunately, the same reperfusion can also contribute to the propagation of brain injury initiated by the HI insult. This implies that HI brain injury as a disease, consists of two fundamental pathophysiological events: hypoxia-ischemia and reperfusion. During hypoxia-ischemia and reperfusion mitochondrial dysfunction plays a fundamental role in brain injury. It is now recognized that not only mitochondrial failure to generate ATP during ischemia, but the generation of oxidative radicals and the release of proapoptotic proteins during reperfusion contribute to the
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