Atomistic simulations indicate the c-subunit ring of the F 1 F o ATP synthase is not the mitochondrial permeability transition pore

Elife. 2017 Feb 10;6:e23781. doi: 10.7554/eLife.23781.

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, proposedly 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 formed within the c-subunit ring of the ATP synthase, upon its dissociation from the catalytic domain of the enzyme. 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 quantify the likelihood that the lumen of these c-rings is in a hydrated, potentially conducting state rather than empty or blocked by lipid molecules. These calculations demonstrate that the structure and biophysical properties of a correctly assembled c-ring are inconsistent with those attributed to the MPTP.

Keywords: apoptosis; bioenergetics; biophysics; ion channels; mitochondria; molecular dynamics; none; structural biology.

MeSH terms

  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Proton-Translocating ATPases / chemistry*
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Molecular Dynamics Simulation
  • Saccharomyces cerevisiae / enzymology*

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases

Grant support

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