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

Abstract

37The c subunit is an inner mitochondrial membrane (IMM) protein and is an integral part of the 38 F0 complex of the ATP synthase. Under physiological conditions, this short 75 residue-long 39 peptide folds into an a-helical hairpin and forms oligomers spanning the lipid bilayer. In 40 addition to its physiological role, the c subunit has been proposed as a key participant in stress-41 induced IMM permeabilization by the mechanism of calcium-induced permeability transition. 42 However, the molecular mechanism of the c subunit participation in IMM permeabilization is 43 not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy 44 and black lipid membrane methods to gain insights into the structural and functional properties 45 of c subunit protein that make it relevant to mitochondrial toxicity. We discovered that c 46 subunit is an amyloidogenic peptide that can spontaneously fold into b-sheets and self-47 assemble into fibrils and oligomers. C subunit oligomers exhibited ion channel activity in lipid 48 membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic 49properties and are driven by mechanisms similar to those of neurodegenerative polypeptides 50 such as Aβ and a-synuclein. 51 52 53