Aging enhances the activation of the permeability transition pore in mitochondria

Aging is associated with mitochondrial dysfunction in several tissues. However, it is not known how the observed mitochondrial dysfunction is related to aging-associated tissue degeneration. We have shown previously that the activation of the permeability transition pore (PTP), which is believed to play a critical role in cell necrosis and apoptosis, is enhanced in spleen lymphocytes from old mice. Here we show that the threshold for calcium-induced, cyclosporin-sensitive, calcium release was significantly lower in isolated brain and liver mitochondria from aging mice. Thus, aging mice exhibit enhanced PTP activation in lymphocytes, brain, and liver. These results suggest that aging increases the susceptibility to calcium-dependent cell death (e.g., excitotoxicity, ischemia-reperfusion damage) in the brain, liver, and possibly other tissues. In addition, other pathways to apoptosis or necrosis that depend on PTP activation are also likely to be enhanced by aging.