Acidosis promotes the permeability transition in energized mitochondria: Implications for reperfusion injury

We have studied the influence of pH on opening of the mitochondrial permeab ility transition pore (PTP) in both deenergized and energized mitochondria. in the presence of P-i. In deenergized mitochondria from rat brain and hea rt, we observed the expected inhibition of Ca2+-induced PTP opening at incr easingly acidic pH values. Unexpectedly, mitochondria energized with either electron transport complex I or complex II substrates displayed the opposi te behavior, acidic pH promoting rather than inhibiting PTP opening. We sho w that the potentiating effect of acidic pH is due to an increased rate of P-i uptake. The data also revealed that brain mitochondria are more heterog eneous than heart or liver mitochondria in relation to onset of a permeabil ity transition, and that this heterogeneity depends on their P-i transport capacity. Taken together, these results indicate that the inhibitory effect s of acidic pH on the PTP may be overcome in situ by an increased rate of P i uptake, and that ischemic and postischemic acidosis may worsen rather tha n relieve PTP-dependent tissue damage.