Apoptotic cell death has been shown to constitute the terminal process in some neurodegenerative diseases, notably Alzheimer's disease and Parkinson's disease (PD). A decrease in mitochondrial membrane potential (delta psiM) causing opening of the permeability transition pore (PTP) in mitochondrial membranes has been implicated as a critical effector of apoptosis in a variety of non-neural cells. Opening of the PTP leads to the release of so-called apoptosis initiation factors that induce the degradative events of apoptosis, such as nuclear chromatin condensation and DNA fragmentation. We have extended those findings to a neuronal model of apoptosis caused by trophic withdrawal, by showing that a decrease in delta psiM is an early event occurring 2 to 6 hours before the degradative events of apoptosis. A deficiency in mitochondrial complex I activity has been demonstrated in the substantia nigra of postmortem brains and several peripheral tissues obtained from PD patients. Because delta psiM is generated by the pumping of protons out across the inner mitochondrial membrane at the mitochondrial complexes, particularly complex I, we hypothesized that the decrease in complex activity could result in a decrease in delta psiM that would render PD substantia nigra neurons vulnerable to apoptosis. In preliminary studies, we have found a decrease in delta psiM in fibroblasts obtained from some PD patients. If a decrease in delta psiM consequent on decreased complex activity is an intrinsic defect in some PD patients, it would open a number of new avenues for the reduction of neuronal apoptosis in PD. The oncoprotein BCL-2 and the scavenger protein SOD-1 have been shown to reduce apoptosis by facilitating closure of the PTP. A number of agents have been shown to maintain BCL-2 and/or SOD-1 synthesis in damaged nerve cells and thereby reduce apoptosis. Other agents, such as cyclosporin A and some benzodiazepine receptor-binding agents, have been found to act directly on the PTP to reduce apoptosis. Accordingly, agents that maintain delta psiM and PTP closure may offer new and effective means of treating neurodegenerative apoptosis.