Four lines of evidence suggest that mitochondrial function is degraded, and may constitute the agonal cellular event after traumatic brain injury: 1) mitochondrial swelling is seen on ultrastructural analysis in both humans and animal models; 2) lactate in traumatized tissues remains high, even when regional cerebral blood flow is normal suggesting inadequate oxidative metabolism; 3) oxygen utilization is reduced in traumatized brain tissue components of the oxidative phosphorylation pathway on the inner-membrane, and the permeability transition pore, suggests that they maybe especially vulnerable to mechanical disruption, even to a minor degree and may be thus rendered functionally degraded, as supported by our pilot studies, in Subproject 4. Furthermore, the increases in intracellular calcium, demonstrated in both TBI and ischemia, and the known sensitivity of mitochondrial function to calcium flux, mediated via the permeability transition pore, support this concept. We, therefore, hypothesize designed to prevent opening of the mitochondrial transition pore, support this concept. We, therefore, hypothesize that the therapy designed to prevent opening of the mitochondrial transition pore, in response to trauma-induced calcium ion flux, may improve mitochondrial function after traumatic brain injury, thus providing more ATP, for restoration of ionic homeostasis. We further posit, based upon our pilot data, that rapid consumption of lactate. We will, therefore, perform focused studies to test the effect of brain tissue oxygen enhancement, and Cyclosporin A, a blocker of the mitochondrial transition pore in severe human head injury using a variety of newly developed endpoints, in order to demonstrate a therapeutic biological effect of these two new putative therapies for traumatic brain injury.