An innovative approach for a rare disease Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare, inherited neurodegenerative condition. Affected individuals develop severe progressive muscle weakness, motor deficits, and peripheral neuropathy. Although defects in the gene encoding mitofusin 2 (MFN2) are known to cause CMT2A, the disease remains incurable. Rocha et al. identified specific MFN2 residues contributing to the disease and developed a class of MFN2-agonist drugs. The small molecules restored mitochondrial fusion and activity in the sciatic nerves of mice; they may also help in other diseases linked to mitochondrial trafficking. Science, this issue p. 336 New insights provide a lead that may help to produce treatments for mitochondrial disease. Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase–mediated phosphorylation of adjacent MFN2 Ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94→Gln94 and MFN2 Thr105→Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.

中文翻译：

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MFN2 激动剂逆转 Charcot-Marie-Tooth 病 2A 型临床前模型中的线粒体缺陷

一种罕见疾病 Charcot-Marie-Tooth 2A 型 (CMT2A) 的创新方法是一种罕见的遗传性神经退行性疾病。受影响的个体会出现严重的进行性肌肉无力、运动障碍和周围神经病变。尽管已知编码丝裂蛋白 2 (MFN2) 的基因缺陷会导致 CMT2A，但该疾病仍然无法治愈。罗查等人。确定了导致该疾病的特定 MFN2 残基，并开发了一类 MFN2 激动剂药物。小分子恢复了小鼠坐骨神经中的线粒体融合和活性；它们还可能有助于治疗与线粒体贩卖有关的其他疾病。科学，这个问题 p。336 新见解提供了可能有助于产生线粒体疾病治疗方法的先导。Mitofusins (MFNs) 促进融合介导的线粒体内容交换和亚细胞运输。Mfn2 突变导致神经退行性夏科-玛丽-牙病 2A 型 (CMT2A)。我们发现 MFN2 活性可以通过 Met376 和 His380 与 Asp725 和 Leu727 的相互作用来确定，并受 PINK1 激酶介导的相邻 MFN2 Ser378 磷酸化控制。MFN2 肽-肽界面的小分子模拟物破坏了这种相互作用，变构激活 MFN2 并促进线粒体融合。这些一流的线粒体融合蛋白激动剂克服了 CMT2A 突变体 MFN2 Arg94→Gln94 和 MFN2 Thr105→Met105 在培养的神经元中引起的显性线粒体缺陷，如线粒体运动障碍、碎裂、去极化和结块的改善所证明的。