An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore
Stressful cellular events cause intracellular Ca2+ dysregulation, rapid loss of inner mitochondrial membrane potential [the permeability transition (PT)], metabolic dysfunction, and death. Rapid Ca2+-induced uncoupling is one of the most important regulators of cell demise. We show that the c-subunit ring of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to PT and cell death. In contrast, c-subunit channel closure promotes cell survival and increased efficiency of cellular metabolism. The c-subunit channel is therefore strategically located at the center of the energy-producing complex of the cell to regulate metabolic efficiency and orchestrate the rapid onset of death and thus is a candidate for the mitochondrial PT pore.