Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore

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Abstract

Pathological metabolic conditions such as ischemia induce the rupture of the mitochondrial envelope and the release of pro-apoptotic proteins, leading to cell death. At the onset of this process, the inner mitochondrial membrane becomes depolarized and permeable to osmolytes, due to the opening of a non-selective protein channel of unknown molecular identity. A recent study purports that this channel, referred to as Mitochondrial Permeability Transition Pore (MPTP), is the lumen of the c-subunit ring of the ATP synthase, upon dissociation from the catalytic domain. Here, we examine this claim for two c-rings of different lumen width, through calculations of their ion conductance and selectivity based on all-atom molecular dynamics simulations. We also evaluate the likelihood that this lumen is hydrated rather than empty or blocked by lipid molecules. These calculations demonstrate that the properties of the lumen of a correctly assembled c-ring are inconsistent with those attributed to the MPTP.

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Wenchang Zhou

Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0397-1032
Fabrizio Marinelli

Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States

For correspondence
fabrizio.marinelli@nih.gov

Competing interests
The authors declare that no competing interests exist.
Corrine Nief

Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
José D Faraldo-Gómez

Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States

For correspondence
jose.faraldo@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7224-7676

Funding

National Heart, Lung, and Blood Institute

Wenchang Zhou
José D Faraldo-Gómez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.