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

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

Vollum Institute

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Article number	108095
Journal	Cell Reports
Volume	32
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.108095
State	Published - Sep 1 2020

Keywords

F-ATP synthase
OSCP
cyclophilin D
cysteine
mitochondria
oxidation
permeability transition pore

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2020.108095

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

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",

author = "Michela Carraro and Kristen Jones and Geppo Sartori and Marco Schiavone and Salvatore Antonucci and Roza Kucharczyk and {di Rago}, {Jean Paul} and Cinzia Franchin and Giorgio Arrigoni and Michael Forte and Paolo Bernardi",

note = "Funding Information: This research was funded by the Italian Association for Cancer Research ( AIRC ; grant IG17067 ), Fondation Leducq ( 16CVD04 ), and the Ministry for the University and Research, Italy ( 2017LHFW42 ). Publisher Copyright: {\textcopyright} 2020 The Author(s)",

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AU - Carraro, Michela

AU - Jones, Kristen

AU - Sartori, Geppo

AU - Schiavone, Marco

AU - Antonucci, Salvatore

AU - Kucharczyk, Roza

AU - di Rago, Jean Paul

AU - Franchin, Cinzia

AU - Arrigoni, Giorgio

AU - Forte, Michael

AU - Bernardi, Paolo

N1 - Funding Information: This research was funded by the Italian Association for Cancer Research ( AIRC ; grant IG17067 ), Fondation Leducq ( 16CVD04 ), and the Ministry for the University and Research, Italy ( 2017LHFW42 ). Publisher Copyright: © 2020 The Author(s)

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - F-ATP synthase

KW - OSCP

KW - cyclophilin D

KW - cysteine

KW - mitochondria

KW - oxidation

KW - permeability transition pore

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

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