Mitochondrial participation in ischemic and traumatic neural cell death

Mitochondria play critical roles in cerebral energy metabolism and in the regulation of cellular Ca2+ homeostasis. They are also the primary intracellular source of reactive oxygen species, due to the tremendous number of oxidation-reduction reactions and the massive utilization of O2 that occur there. Metabolic trafficking among cells is also highly dependent upon normal, well-controlled mitochondrial activities. Alterations of any of these functions can cause cell death directly or precipitate death indirectly by compromising the ability of cells to withstand stressful stimuli. Abnormal accumulation of Ca2+ by mitochondria in response to exposure of neurons to excitotoxic levels of excitatory neurotransmitters, for example, glutamate, is a primary mediator of mitochondrial dysfunction and delayed cell death. Excitoxicity, along with inflammatory reactions, mechanical stress, and altered trophic signal transduction, all likely contribute to mitochondrial damage observed during the evolution of traumatic brain injury. The release of apoptogenic proteins from mitochondria into the cytosol serves as a primary mechanism responsible for inducing apoptosis, a form of cell death that contributes significantly to neurologic impairment following neurotrauma. Although several signals for the release of mitochondrial cell death proteins have been identified, the mechanisms by which these signals increase the permeability of the mitochondrial outer membrane to apoptogenic proteins is controversial. Elucidation of the precise biochemical mechanisms responsible for mitochondrial dysfunction during neurotrauma and the roles that mitochondria play in both necrotic and apoptotic cell death should provide new molecular targets for neuroprotective interventions.