The human mitochondrial DNA depletion syndrome gene MPV17 encodes a non-selective channel that modulates membrane potential

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p>The human <em>MPV17</em>-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein <em>MPV17</em>. Although more than 30 <em>MPV17</em> gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of <em>MPV17</em> is still unknown. Mice deficient in <em>Mpv17</em> show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant <em>MPV17</em> 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 (Δψ_m) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from <em>Mpv17</em>^−/− mice. However, despite the elevated Δψ_m, the <em>Mpv17</em>-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of <em>MPV17</em> as a Δψ_m-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.</p></div>