The Human mtDNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel that Modulates Membrane Potential [Bioenergetics]

April 10th, 2015 by Antonenkov, V. D., Isomursu, A., Mennerich, D., Vapola, M. H., Weiher, H., Kietzmann, T., Hiltunen, J. K.

The human MPV17-related mitochondrial DNA depletion syndrome (MDDS) 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 MDDS, 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 sub-conductance states. Voltage-dependent gating of the channel was regulated by redox conditions, pH, and affected in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Delta Psi m) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17-/- mice. However, despite of the elevated Delta Psi m, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Delta Psi m modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.