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

Giuseppe Federico Amodeo,Zoya Leonenko,Brenda Yasie Lee,Sergey Noskov,Daniel Erik Otzen,Evgeny V Pavlov,Natalya Krilyuk,Carina Teresa Filice,Denis Valyuk

doi:10.1038/s41598-021-88157-z

Giuseppe Federico Amodeo, Zoya Leonenko + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-88157-z

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Abstract

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.

Highlights

The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes
Our study found that the c subunit is an amyloidogenic peptide that has the ability to fold into a β-sheet conformation and form fibrils or oligomers in a calcium dependent manner
We hypothesize that the mechanism of c subunit toxicity on mitochondrial membranes occurs through structural rearrangements similar to those described for other amyloidogenic polypeptides including Aβ (Alzheimer’s Disease) and α-synuclein (Parkinson’s Disease) and possibly other synucleopathies[17,18,19]

Summary

Introduction

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 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. We propose the possibility that in addition to its role in native conditions, c subunit could exert a pathological action on mitochondria through its misfolded oligomers Based on these findings, we hypothesize that the mechanism of c subunit toxicity on mitochondrial membranes occurs through structural rearrangements similar to those described for other amyloidogenic polypeptides including Aβ (Alzheimer’s Disease) and α-synuclein (Parkinson’s Disease) and possibly other synucleopathies[17,18,19]

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Conclusion