ATP Synthase C-Subunit-Deficient Mitochondria Have a Small Cyclosporine A-Sensitive Channel, but Lack the Permeability Transition Pore

Maria A Neginskaya,Maria E Solesio,Elena V Berezhnaya,Giuseppe F Amodeo,Nelli Mnatsakanyan,Elizabeth A Jonas,Evgeny V Pavlov

doi:10.1016/j.celrep.2018.12.033

Maria A Neginskaya, Maria E Solesio + Show 5 more

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https://doi.org/10.1016/j.celrep.2018.12.033

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Journal: Cell Reports	Publication Date: Jan 1, 2019
Citations: 142	License type: cc-by

Affiliation: New York University, Yale University

Abstract

SUMMARYPermeability transition (PT) is an increase in mitochondrial inner membrane permeability that can lead to a disruption of mitochondrial function and cell death. PT is responsible for tissue damage in stroke and myocardial infarction. It is caused by the opening of a large conductance (~1.5 nS) channel, the mitochondrial PT pore (mPTP). We directly tested the role of the c-subunit of ATP synthase in mPTP formation by measuring channel activity in c-subunit knockout mitochondria. We found that the classic mPTP conductance was lacking in c-subunit knockout mitochondria, but channels sensitive to the PT inhibitor cyclosporine A could be recorded. These channels had a significantly lower conductance compared with the cyclosporine A-sensitive channels detected in parental cells and were sensitive to the ATP/ADP translocase inhibitor bongkrekic acid. We propose that, in the absence of the c-subunit, mPTP cannot be formed, and a distinct cyclosporine A-sensitive low-conductance channel emerges.

Highlights

Mitochondrial permeability transition (PT) is the phenomenon of a dramatic increase in the permeability of the mitochondrial inner membrane
MPTP Channel Activity Is Evoked by Calcium in WildType Mitochondria Isolated from Wild-Type HAP1 Cells Containing the C-Subunit To study channel activity associated with Permeability transition (PT), we used mitochondria isolated from cultured HAP1 cells (He et al, 2017b)
cyclosporine A (CSA)-Sensitive Channel Activity of C-Subunit Knockout Mitochondria Has Low Conductance we investigated the ion channel activity of the mutant mitochondria from HAP1-A12 cells lacking the c-subunit of the ATP synthase

Summary

Introduction

Mitochondrial permeability transition (PT) is the phenomenon of a dramatic increase in the permeability of the mitochondrial inner membrane. It is established that PT is caused by the opening of a large channel (mitochondrial PT pore, or mPTP) in the inner membrane. It has been proposed that the pore is directly formed by the c-subunit ring (Alavian et al, 2014), oligomers of the c-subunit of the ATP synthase (Bonora et al, 2017; Jonas et al, 2015), by assembly of c-subunit/polyphosphate/polyhydroxybutyrate complex (Elustondo et al, 2016; Pavlov et al, 2005), or by a putative channel-forming structure localized in between two monomers of this enzyme (Bernardi et al, 2015). We propose that in the absence of the c-subunit, the large conductance mPTP channel cannot form, but opening of other CSA-sensitive channels may contribute to depolarization of the inner mitochondrial membrane

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