title: The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential.
abstract: The human MPV17-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17. Although more than 30 MPV17 gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of MPV17 is still unknown. Mice deficient in Mpv17 show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant MPV17 to reveal that this protein forms a non-selective channel with a pore diameter of 1.8 nm and located the channel's selectivity filter. The channel was weakly cation-selective and showed several subconductance states. Voltage-dependent gating of the channel was regulated by redox conditions and pH and was affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and vasily.antonenkov@oulu.fi.
authors: Vasily D
authors: VD
authors: Antonenkov
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and.
authors: Antti
authors: A
authors: Isomursu
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and.
authors: Daniela
authors: D
authors: Mennerich
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and.
authors: Miia H
authors: MH
authors: Vapola
authors: the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors: Hans
authors: H
authors: Weiher
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and.
authors: Thomas
authors: T
authors: Kietzmann
authors: From the Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland and kalervo.hiltunen@oulu.fi.
authors: J Kalervo
authors: JK
authors: Hiltunen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D002942:Circular Dichroism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005452:Fluoresceins / Q000737:chemistry; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010766:Phosphorylation; D010802:Phylogeny; D010843:Pichia / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D005452:Fluoresceins; C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C029569:diacetyldichlorofluorescein
keywords: Mpv17 protein; aging; membrane protein; mitochondria; mitochondrial DNA damage; mitophagy; non-selective channel