The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential
The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential
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DOI：
10.1074/jbc.m114.608083
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发表时间：
2015-05-29
影响因子：
4.8
通讯作者：
Hiltunen, J. Kalervo
中科院分区：
文献类型：
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作者：
Antonenkov, Vasily D.;Isomursu, Antti;Hiltunen, J. Kalervo
人类MPV 17相关线粒体DNA缺失综合征是一种由线粒体内膜蛋白MPV 17突变引起的遗传性常染色体隐性遗传疾病。虽然超过30个MPV 17基因突变被证明与线粒体DNA耗竭综合征相关，但MPV 17的功能仍然未知。缺乏Mpv 17的小鼠表现出过早衰老的迹象。在本研究中，我们使用重组MPV 17的电生理学测量，揭示这种蛋白质形成了一个非选择性通道，孔径为1.8 nm，并定位通道的选择性过滤器。该通道是弱阳离子选择性，并表现出几个亚电导状态。电压依赖性门控的通道调节氧化还原条件和pH值，也受到影响的突变体模仿磷酸化状态。同样，线粒体膜电位（Δ psi（m））和细胞产生的活性氧更高的胚胎成纤维细胞从Mpv 17（-/-）小鼠。然而，尽管Δ psi（m）升高，但Mpv 17缺陷型线粒体显示出加速分裂的迹象。总之，这些观察揭示了MPV 17作为Delta psi（m）调节通道的作用，其在不同条件下显然有助于线粒体稳态。
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 (Delta psi(m)) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite 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.