A Novel Ion Channel in ATP Synthase C-Subunit Ring: Gatekeeper of Life and Death

Abstract

Mitochondria play a central role in ageing, cardiac disease, cell death and cancer. Different pro-death signals lead to the permeabilization of the outer and inner mitochondrial membranes. Permeabilization of the inner mitochondrial membrane is facilitated by the mitochondrial permeability transition pore (mPTP), which is a key player in activation of cell death pathways. mPTP is a voltage and Ca2+-dependent high conductance channel. The brief opening of mPTP may serve physiological functions, but its prolonged opening leads to swelling of the mitochondrial matrix, rupture of outer and inner membranes and eventually to cell death. In spite of critical roles played by mPTP, its molecular nature remains mysterious and was a subject of scientific debate for many years. We recently demonstrated that the membrane-embedded c-subunit ring of F1FO-ATP synthase can form an uncoupling channel with biophysical characteristics of mPTP, nevertheless the conformational changes in ATP synthase leading to the opening of the c-subunit channel are still poorly understood. We have used site-directed mutagenesis accompanied by patch clamp recording as well as protein-protein interaction studies to gain a new understanding of the gating mechanism of the c-subunit leak channel. We have also expressed wild-type and mutant c-subunit channels in primary hippocampal neurons to study the role of the c-subunit channel in neuronal cell death, neuronal function and survival. We present a novel structural-functional model of mPTP gating by highlighting the molecular mechanisms and conformational changes in the F1FO-ATP synthase necessary to open the c-subunit channel.