ATP synthase c-subunit ring as the channel of mitochondrial permeability transition: Regulator of metabolism in development and degeneration

The mitochondrial permeability transition pore (mPTP) or mitochondrial megachannel is arguably one of the most mysterious phenomena in biology today. mPTP has been at the center of ongoing extensive scientific research for the last several decades. In this review we will discuss recent advances in the field that enhance our understanding of the molecular composition of mPTP, its regulatory mechanisms and its pathophysiological role. We will describe our recent findings on the role of ATP synthase c-subunit ring as a central player in mitochondrial permeability transition and as an important metabolic regulator during development and in degenerative diseases. •ATP synthase c-subunit is the leak channel of mitochondrial permeability transition.•c-subunit channel is the master regulator of cell metabolism in embryonic and synaptic development.•F1/FO stoichiometry change is critical for c-subunit regulatory function.•Non-reversible dissociation of ATP synthase F1 from FO triggers age-related ischemic and degenerative diseases.•We discuss models for ATP synthase channel gating in physiological and pathological conditions.