Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-Ku, Kyoto, 606-8585, Japan.
Advanced Insect Research Promotion Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-Ku, Kyoto, 606-8585, Japan.
Sci Rep. 2022 Dec 31;12(1):22632. doi: 10.1038/s41598-022-27329-x.
Mutations in the Mpv17 gene are responsible for MPV17-related hepatocerebral mitochondrial DNA depletion syndrome and Charcot-Marie-Tooth (CMT) disease. Although several models including mouse, zebrafish, and cultured human cells, have been developed, the models do not show any neurological defects, which are often observed in patients. Therefore, we knocked down CG11077 (Drosophila Mpv17; dMpv17), an ortholog of human MPV17, in the nervous system in Drosophila melanogaster and investigated the behavioral and cellular phenotypes. The resulting dMpv17 knockdown larvae showed impaired locomotor activity and learning ability consistent with mitochondrial defects suggested by the reductions in mitochondrial DNA and ATP production and the increases in the levels of lactate and reactive oxygen species. Furthermore, an abnormal morphology of the neuromuscular junction, at the presynaptic terminal, was observed in dMpv17 knockdown larvae. These results reproduce well the symptoms of human diseases and partially reproduce the phenotypes of Mpv17-deficient model organisms. Therefore, we suggest that neuron-specific dMpv17 knockdown in Drosophila is a useful model for investigation of MPV17-related hepatocerebral mitochondrial DNA depletion syndrome and CMT caused by Mpv17 dysfunction.
Mpv17 基因突变是导致 MPV17 相关肝脑线粒体 DNA 耗竭综合征和 Charcot-Marie-Tooth (CMT) 疾病的原因。尽管已经开发了包括小鼠、斑马鱼和培养的人类细胞在内的几种模型,但这些模型均未显示出患者中经常观察到的任何神经缺陷。因此,我们在黑腹果蝇的神经系统中敲低了 CG11077(果蝇 Mpv17;dMpv17),这是人类 MPV17 的同源物,并研究了其行为和细胞表型。结果表明,dMpv17 敲低幼虫的运动活性和学习能力受损,这与线粒体 DNA 和 ATP 产生减少以及乳酸和活性氧水平升高所提示的线粒体缺陷一致。此外,在 dMpv17 敲低幼虫中观察到神经肌肉接头的前突触末端的异常形态。这些结果很好地再现了人类疾病的症状,并部分再现了 Mpv17 缺陷模型生物的表型。因此,我们建议在果蝇中特异性敲低神经元中的 dMpv17 是研究由 Mpv17 功能障碍引起的 MPV17 相关肝脑线粒体 DNA 耗竭综合征和 CMT 的有用模型。