title: Atomistic simulations indicate the c-subunit ring of the F1FoATP synthase is not the mitochondrial permeability transition pore.
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.
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Wenchang
authors.identifier: 0000-0003-0397-1032
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marinelli
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Corrine
authors.initials: C
authors.lastname: Nief
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: José D
authors.identifier: 0000-0001-7224-7676
authors.initials: JD
authors.lastname: Faraldo-Gómez
mesh_terms: D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases
keywords: apoptosis; bioenergetics; biophysics; ion channels; mitochondria; molecular dynamics; none; structural biology