Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
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DOI：
10.1124/jpet.122.001332
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发表时间：
2022-11
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Mitofusin(MFn)1和Mfn2是动力蛋白GTP酶家族的线粒体蛋白，它们介导需要MFN构象移动的线粒体融合，在线粒体上和线粒体之间形成大分子复合体，以及GTP水解。损伤性Mfn2突变会导致一种无法治疗的、主要是儿科进行性周围神经病变的2A型Charcot-Marie-Tooth(CMT)病。我们使用促进Mfn构象有利于融合的小分子变构丝裂原激活剂，在体外研究Mfn2构象和GTPase活性对Mfn2介导的线粒体融合和运动的影响。我们通过定义丝裂原激活剂在小鼠CMT2A中的剂量依赖药效学和疾病修改效应，在体内翻译了这些发现。Mfn2催化GTP酶活性和Mfn2构象转换是线粒体融合所必需的，但这两个过程是分开的。我们首次报道了丝裂原激活剂刺激线粒体通过CMT2A神经元轴突运输的浓度-反应关系，这类似于它们对线粒体融合的刺激。在CMT2A小鼠中，间歇性(每日短效)和持续(每日两次长效)丝裂原激活在逆转神经肌肉变性方面同样有效。此外，丝裂原激活剂对线粒体通过CMT2A神经轴突运输的急性药效学效应早于神经退行性表型的长期逆转。一项交叉研究表明，停止使用丝裂原激活剂后，CMT2A神经元缺陷会复发，并揭示即使在老年(>；74周)小鼠中，CMT2A也可以通过激活丝裂原蛋白来改善。这些数据增加了我们对CMT2AMfn2 GTPase突变引起的线粒体功能障碍的理解，并为CMT2A中有丝分裂蛋白的药理激活方法提供了额外的信息。本研究探讨了Mfn2催化活性和变构激活在线粒体融合和神经元运输受损方面的作用，因为它们影响了Mfn2突变引起的一种不可治疗的周围神经疾病，即2A型Charcot-Marie-Tooth病。这些结果从机制上将线粒体融合和运动性与松弛的Mfn2蛋白构象和线粒体异常的纠正以及体内CMT2a神经变性的逆转联系在一起。
Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity and MFN2 conformational switching are essential for mitochondrial fusion, but the two processes are separate and dissociable. We report the first concentration-response relationships for mitofusin activators to stimulate mitochondrial transport through CMT2A neuronal axons, which is similar to their stimulation of mitochondrial fusion. In CMT2A mice, intermittent (daily short acting) and sustained (twice daily long acting) mitofusin activation were equally effective in reversing neuromuscular degeneration. Moreover, acute dose-dependent pharmacodynamic effects of mitofusin activators on mitochondrial transport through CMT2A neuronal axons anticipated those for long-term reversal of neurodegenerative phenotypes. A crossover study showed that CMT2A neuronal deficits recurred after mitofusin activators are discontinued, and revealed that CMT2A can be ameliorated by mitofusin activation even in old (>74 week) mice. These data add to our understanding of mitochondrial dysfunction induced by a CMT2A MFN2 GTPase mutation and provide additional information supporting the approach of pharmacological mitofusin activation in CMT2A. This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.
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