The Unique Cysteine of F-ATP Synthase OSCP Subunit Participates in Modulation of the Permeability Transition Pore

Michela Carraro; Kristen Jones; Geppo Sartori; Marco Schiavone; Salvatore Antonucci; Roza Kucharczyk; Jean-Paul di Rago; Cinzia Franchin; Giorgio Arrigoni; Michael Forte; Paolo Bernardi

doi:10.1016/j.celrep.2020.108095

The Unique Cysteine of F-ATP Synthase OSCP Subunit Participates in Modulation of the Permeability Transition Pore

Cell Rep. 2020 Sep 1;32(9):108095. doi: 10.1016/j.celrep.2020.108095.

Authors

Affiliations

¹ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 35131 Padova, Italy. Electronic address: carraro.miche@gmail.com.
² Vollum Institute, OHSU, Portland, OR 97239, USA.
³ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
⁴ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 35131 Padova, Italy.
⁵ Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 00-901 Warsaw, Poland.
⁶ Institut de Biochimie et Génétique Cellulaires and CNRS, UMR 5095, Université de Bordeaux, 33077 Bordeaux, France.
⁷ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35131 Padova, Italy.
⁸ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 35131 Padova, Italy. Electronic address: bernardi@bio.unipd.it.

PMID: 32877677
DOI: 10.1016/j.celrep.2020.108095

Abstract

The mitochondrial permeability transition pore (PTP) is a Ca²⁺-activated channel that plays a key role in cell death. Thiol oxidation facilitates PTP opening, yet the targets and molecular mechanisms still await a definition. Here, we investigate the role of C141 of F-ATP synthase oligomycin sensitivity conferral protein (OSCP) subunit in PTP modulation by oxidation. We find that the OSCP C141S mutation confers resistance to PTP opening and cell death by diamide and MitoParaquat only when cyclophilin D (CyPD) has been ablated, a protective role that can be explained by CyPD shielding C141 from oxidants. The mutation decreases apoptosis in zebrafish embryos, indicating that this OSCP residue is involved in development. Site-directed mutagenesis in yeast suggests that other conserved cysteines in the α, γ, and c subunits of F-ATP synthase are not involved in PTP modulation. Thus, OSCP provides a strategic site that regulates PTP opening by the interplay between CyPD (un)binding and thiol oxidation-reduction.

Keywords: F-ATP synthase; OSCP; cyclophilin D; cysteine; mitochondria; oxidation; permeability transition pore.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cysteine / metabolism*
Humans
Mitochondrial Permeability Transition Pore / metabolism*
Mitochondrial Proton-Translocating ATPases / metabolism*
Permeability*

Substances

Mitochondrial Permeability Transition Pore
Mitochondrial Proton-Translocating ATPases
oligomycin sensitivity-conferring protein
Cysteine