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

  1. Wenchang Zhou
  2. Fabrizio Marinelli  Is a corresponding author
  3. Corrine Nief
  4. José D Faraldo-Gómez  Is a corresponding author
  1. National Heart, Lung and Blood Institute, National Institutes of Health, United States

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.

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0397-1032
  2. 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.
  3. 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.
  4. 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.
    ORCID icon "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.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Publication history

  1. Received: November 30, 2016
  2. Accepted: February 9, 2017
  3. Accepted Manuscript published: February 10, 2017 (version 1)
  4. Version of Record published: February 23, 2017 (version 2)

Copyright

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.

Metrics

  • 1,690
    Page views
  • 461
    Downloads
  • 64
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Wenchang Zhou
  2. Fabrizio Marinelli
  3. Corrine Nief
  4. José D Faraldo-Gómez
(2017)
Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore
eLife 6:e23781.
https://doi.org/10.7554/eLife.23781
  1. Further reading

Further reading

    1. Microbiology and Infectious Disease
    2. Structural Biology and Molecular Biophysics
    Alejandro Villalta, Alain Schmitt ... Chantal Abergel
    Research Article Updated

    Mimivirus is the prototype of the Mimiviridae family of giant dsDNA viruses. Little is known about the organization of the 1.2 Mb genome inside the membrane-limited nucleoid filling the ~0.5 µm icosahedral capsids. Cryo-electron microscopy, cryo-electron tomography, and proteomics revealed that it is encased into a ~30-nm diameter helical protein shell surprisingly composed of two GMC-type oxidoreductases, which also form the glycosylated fibrils decorating the capsid. The genome is arranged in 5- or 6-start left-handed super-helices, with each DNA-strand lining the central channel. This luminal channel of the nucleoprotein fiber is wide enough to accommodate oxidative stress proteins and RNA polymerase subunits identified by proteomics. Such elegant supramolecular organization would represent a remarkable evolutionary strategy for packaging and protecting the genome, in a state ready for immediate transcription upon unwinding in the host cytoplasm. The parsimonious use of the same protein in two unrelated substructures of the virion is unexpected for a giant virus with thousand genes at its disposal.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Chris Furlan, Nipa Chongdar ... James A Birrell
    Research Article Updated

    Electron bifurcation is a fundamental energy conservation mechanism in nature in which two electrons from an intermediate-potential electron donor are split so that one is sent along a high-potential pathway to a high-potential acceptor and the other is sent along a low-potential pathway to a low-potential acceptor. This process allows endergonic reactions to be driven by exergonic ones and is an alternative, less recognized, mechanism of energy coupling to the well-known chemiosmotic principle. The electron-bifurcating [FeFe] hydrogenase from Thermotoga maritima (HydABC) requires both NADH and ferredoxin to reduce protons generating hydrogen. The mechanism of electron bifurcation in HydABC remains enigmatic in spite of intense research efforts over the last few years. Structural information may provide the basis for a better understanding of spectroscopic and functional information. Here, we present a 2.3 Å electron cryo-microscopy structure of HydABC. The structure shows a heterododecamer composed of two independent ‘halves’ each made of two strongly interacting HydABC heterotrimers connected via a [4Fe–4S] cluster. A central electron transfer pathway connects the active sites for NADH oxidation and for proton reduction. We identified two conformations of a flexible iron–sulfur cluster domain: a ‘closed bridge’ and an ‘open bridge’ conformation, where a Zn2+ site may act as a ‘hinge’ allowing domain movement. Based on these structural revelations, we propose a possible mechanism of electron bifurcation in HydABC where the flavin mononucleotide serves a dual role as both the electron bifurcation center and as the NAD+ reduction/NADH oxidation site.