Transient global ischemia in rodents (2 vessel occlusion in mice, 2VO) induces delayed death of hippocampal CA1 neurons and is a model for human ischemic brain injury and long lasting hippocampal memory deficits. Events that occur before neuronal death include caspase and pro-apoptotic Bcl-2 family member (Bax) activation, cleavage of the anti-death Bcl-2 family protein Bcl-xL, cellular Ca2+ dysregulation and large conductance mitochondrial channel activity. The opening of a large conductance, Ca2+ dependent, inner mitochondrial membrane channel occurs early during the injury phase, therefore the identification and targeting of this inner membrane channel has long been an important goal of both basic research and clinical communities. The inner membrane channel is known as the mitochondrial permeability transition pore (mPTP). It is activated by neuronal Ca2+ dysregulation and by the binding of the mitochondrial peptidyl-prolyl cis-trans isomerase cyclophilin D (CypD). It has been reported that CypD binds to the stator region of the ATP synthase at the OSCP subunit. CypD binding is inhibited by the well-known mPTP inhibitor cyclosporine A (CsA), which attenuates mPT channel activation. During the previous funding period, we were the first to demonstrate that the ATP synthase membrane-embedded c-subunit forms the largest known channel of the mPTP, the ATP synthase c-subunit leak channel (ACLC), and we showed that CsA inhibits ACLC activity by binding within the ATP synthase F1/stator portion because channel inhibition fails to occur when the membrane portions of the ATP synthase are chemically stripped of the F1/stator components. We also reported that Dexpramipexole (Dex) is a safe modulator of ATP synthase leak that binds directly to OSCP/subunit b on the stator complex. Dex ameliorates disease in a neurodevelopmental brain disorder. In this current renewal we will focus on the ACLC as the target to inhibit mPTP opening and death. By mutation of the c-subunit to reduce channel activity, we will inhibit ACLC opening and prevent mitochondrial permeability transition (mPT) during glutamate excitotoxicity in neurons and in vivo ischemic brain injury in mice. We will determine if memory loss, a severe, long lasting effect of transient global ischemia in rodents and humans, will be prevented by this genetic strategy.