Reduced mitochondrial membrane potential and altered responsiveness of a mitochondrial membrane megachannel in p53-induced senescence

There is accumulating evidence that mitochondrial membrane potential (Delta Psi(M)) is reduced in aged cells. In addition, a decrease of Delta Psi(M) has been shown to be an early event in many forms of apoptosis. Here we use a mitochondrial potentiometric dye with in situ laser scanning confocal microscopic (LSCM) imaging to demonstrate that Delta Psi(M) is dramatically decreased in both the p53-overexpressing, senescent Ed tumor cells and in pre-apoptotic PC12 cells compared to controls. Treatment with cyclosporin A (CSA), which facilitates closure of the mitochondrial permeability transition pore (PTP), was able to reverse the decrease in Delta Psi(M), in pre-apoptotic PC12 cells but not in the senescent EJ-p53 cells, The capacity to prevent dissipation of Delta Psi(M) in response to agents that facilitate PTP closure may differentiate cells entering apoptosis from those participating in senescence. Therefore, regulation of the closure of the mitochondrial PTP in the presence of decreased Delta Psi(M) may be a decisional checkpoint in distinguishing between growth arrest pathways, (C) 1999 Academic Press.