C subunit of the ATP synthase is an amyloidogenic channel-forming peptide: possible implications in mitochondrial pathogenesis

The c subunit is an inner mitochondrial membrane (IMM) protein and is an integral part of the F0 complex of the ATP synthase. Under physiological conditions, this short 75 residue-long peptide folds into an -helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of c subunit protein that make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into {beta}-sheets and self-assemble into fibrils and oligomers. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as A{beta} and -synuclein.