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C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition

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  • Giuseppe Federico Amodeo, New York University College of Dentistry
  • ,
  • Brenda Yasie Lee, University of Waterloo
  • ,
  • Natalya Krilyuk, New York University College of Dentistry
  • ,
  • Carina Teresa Filice, University of Waterloo
  • ,
  • Denis Valyuk, New York University College of Dentistry
  • ,
  • Daniel Erik Otzen
  • Sergey Noskov, University of Calgary
  • ,
  • Zoya Leonenko, University of Waterloo
  • ,
  • Evgeny V Pavlov, New York University College of Dentistry

The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-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 unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into β-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. 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 Aβ and α-synuclein.

Original languageEnglish
Article number8744
JournalScientific Reports
Number of pages10
Publication statusPublished - Apr 2021

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