MRC Toxicology Unit, University of Cambridge, Lancaster Road, Leicester, LE1 9HN, UK.
Cell Death Dis. 2019 Mar 25;10(4):288. doi: 10.1038/s41419-019-1496-2.
Mutations in the mitochondrial GTPase mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2A), a form of peripheral neuropathy that compromises axonal function. Mitofusins promote mitochondrial fusion and regulate mitochondrial dynamics. They are also reported to be involved in forming contacts between mitochondria and the endoplasmic reticulum. The fruit fly, Drosophila melanogaster, is a powerful tool to model human neurodegenerative diseases, including CMT2A. Here, we have downregulated the expression of the Drosophila mitofusin (dMfn RNAi) in adult flies and showed that this activates mitochondrial retrograde signalling and is associated with an upregulation of genes involved in folic acid (FA) metabolism. Additionally, we demonstrated that pharmacological and genetic interventions designed to increase the FA metabolism pathway suppresses the phenotype of the dMfn RNAi flies. We conclude that strategies to increase FA metabolism may ameliorate diseases, such as peripheral neuropathies, that are associated with loss of mitochondrial function. A video abstract for this article is available at https://youtu.be/fs1G-QRo6xI .
线粒体 GTP 酶融合蛋白 2（MFN2）的突变导致 2 型腓骨肌萎缩症（CMT2A），这是一种周围神经病，会损害轴突功能。融合蛋白促进线粒体融合并调节线粒体动力学。它们也被报道参与形成线粒体和内质网之间的接触。果蝇，黑腹果蝇，是一种强大的工具，可以模拟人类神经退行性疾病，包括 CMT2A。在这里，我们在成年果蝇中下调了果蝇融合蛋白（dMfn RNAi）的表达，结果表明这激活了线粒体逆行信号，并与叶酸（FA）代谢相关基因的上调有关。此外，我们证明，旨在增加 FA 代谢途径的药理学和遗传学干预可以抑制 dMfn RNAi 果蝇的表型。我们得出结论，增加 FA 代谢的策略可能会改善与线粒体功能丧失相关的疾病，如周围神经病。https://youtu.be/fs1G-QRo6xI 提供了本文的视频摘要。
