The C-Subunit Ring Of The F1fo Atp Synthase Constitutes A Leak Channel That Regulates Cellular Metabolic Efficiency By Counteracting The Hd Translocator

The F1FO ATP synthase is a multiple protein mitochondrial inner membrane complex that is responsible for the production of energy in the form of ATP for eukaryotic cells. It is known that the efficiency of ATP production by the F1FO ATP synthase is attenuated by an inner mitochondrial membrane leak of hydrogen ions. Previous work has shown that this leak is regulated and that its modulation protects neurons from cell death stimuli. Nevertheless, the exact molecular identity of the proton leak channel is unknown. Herein we describe, using electrophysiological techniques, a previously undetected non-selective ion channel in the c-subunit ring of the ATP synthase. The channel conductance is markedly decreased by adenine nucleotides and blocked by recombinant beta-subunit of the synthase. Mutation of highly conserved glycine residues within the putative channel pore increases channel conductance, attenuates responses to ATP, and compromises cell function leading to cell death. We conclude that the c-subunit ring is a highly regulated ion channel that can leak protons and other cations in order to regulate the degree of metabolic efficiency. The channel activity described in this work is different from the known characteristics of H+ tranlocator. We predict that normal c-subunit leak channel activity may become compromised during pathological events, disrupting inner membrane integrity.