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The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential

  • 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 (Deltapsim) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite the elevated Deltapsim, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Deltapsim-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.

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Metadaten
Document Type:Article
Language:English
Author:Vasily D. Antonenkov, Antti Isomursu, Daniela Mennerich, Miia H. Vapola, Hans Weiher, Thomas Kietzmann, J. Kalervo Hiltunen
Parent Title (English):J Biol Chem. (The Journal of Biological Chemistry)
Volume:290
Issue:22
First Page:13840
Last Page:13861
ISSN:0021-9258
DOI:https://doi.org/10.1074/jbc.M114.608083
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25861990
Publisher:American Society for Biochemistry and Molecular Biology
Date of first publication:2015/05/29
Departments, institutes and facilities:Institut für funktionale Gen-Analytik (IfGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2018/09/21