title: Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase.
abstract: The permeability transition in human mitochondria refers to the opening of a nonspecific channel, known as the permeability transition pore (PTP), in the inner membrane. Opening can be triggered by calcium ions, leading to swelling of the organelle, disruption of the inner membrane, and ATP synthesis, followed by cell death. Recent proposals suggest that the pore is associated with the ATP synthase complex and specifically with the ring of c-subunits that constitute the membrane domain of the enzyme's rotor. The c-subunit is produced from three nuclear genes,ATP5G1,ATP5G2, andATP5G3, encoding identical copies of the mature protein with different mitochondrial-targeting sequences that are removed during their import into the organelle. To investigate the involvement of the c-subunit in the PTP, we generated a clonal cell, HAP1-A12, from near-haploid human cells, in whichATP5G1,ATP5G2, andATP5G3were disrupted. The HAP1-A12 cells are incapable of producing the c-subunit, but they preserve the characteristic properties of the PTP. Therefore, the c-subunit does not provide the PTP. The mitochondria in HAP1-A12 cells assemble a vestigial ATP synthase, with intact F1-catalytic and peripheral stalk domains and the supernumerary subunits e, f, and g, but lacking membrane subunits ATP6 and ATP8. The same vestigial complex plus associated c-subunits was characterized from human 143B ρ0cells, which cannot make the subunits ATP6 and ATP8, but retain the PTP. Therefore, none of the membrane subunits of the ATP synthase that are involved directly in transmembrane proton translocation is involved in forming the PTP.
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom.
authors.forename: Jiuya
authors.initials: J
authors.lastname: He
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom.
authors.forename: Holly C
authors.initials: HC
authors.lastname: Ford
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom.
authors.forename: Joe
authors.initials: J
authors.lastname: Carroll
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom.
authors.forename: Shujing
authors.initials: S
authors.lastname: Ding
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearnley
authors.affiliation: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom walker@mrc-mbu.cam.ac.uk.
authors.forename: John E
authors.identifier: 0000-0001-7929-2162
authors.initials: JE
authors.lastname: Walker
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001692:Biological Transport; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D010539:Permeability
chemical_list: D007527:Isoenzymes; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP synthase; ATP5G; human mitochondria; permeability transition pore; subunit c