Mitochondrial ATP Synthase C-subunit Leak Channel Triggers Cell Death Upon Loss of Its F Subcomplex

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2022 Mar 24

PMID 35322203

Authors

Nelli Mnatsakanyan

Han-A Park

Jing Wu

Xiang He

Marc C Llaguno

Maria Latta

Paige Miranda

Besnik Murtishi

Morven Graham

Joachim Weber

Richard J Levy

Evgeny V Pavlov

Elizabeth A Jonas

Affiliations

Soon will be listed here.

Abstract

Mitochondrial ATP synthase is vital not only for cellular energy production but also for energy dissipation and cell death. ATP synthase c-ring was suggested to house the leak channel of mitochondrial permeability transition (mPT), which activates during excitotoxic ischemic insult. In this present study, we purified human c-ring from both eukaryotic and prokaryotic hosts to biophysically characterize its channel activity. We show that purified c-ring forms a large multi-conductance, voltage-gated ion channel that is inhibited by the addition of ATP synthase F subcomplex. In contrast, dissociation of F from F occurs during excitotoxic neuronal death suggesting that the F constitutes the gate of the channel. mPT is known to dissipate the osmotic gradient across the inner membrane during cell death. We show that ATP synthase c-subunit knock down (KD) prevents the osmotic change in response to high calcium and eliminates large conductance, Ca and CsA sensitive channel activity of mPT. These findings elucidate the gating mechanism of the ATP synthase c-subunit leak channel (ACLC) and suggest how ACLC opening is regulated by cell stress in a CypD-dependent manner.

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