Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model
Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model
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DOI：
10.1172/jci124194
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发表时间：
2019-04-01
影响因子：
15.9
通讯作者：
Baloh, Robert H.
中科院分区：
文献类型：
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作者：
Zhou, Yueqin;Carmona, Sharon;Baloh, Robert H.
线粒体融合蛋白-2（MFN 2）是一种线粒体外膜蛋白，在大多数组织的线粒体动力学中发挥关键作用，但MFN 2突变会导致Charcot-Marie-Tooth病2A型（CMT 2A），主要影响神经系统。我们产生了CMT 2A的转基因小鼠模型，其发展了严重的早发性视力丧失和神经缺陷，轴突变性而无细胞体损失，以及碎片化线粒体的细胞质和轴突积累。虽然线粒体聚集体被标记为线粒体自噬，但突变体MFN 2不抑制帕金森介导的降解，而是对线粒体具有显性负效应！只有当MFN 1处于低水平时，融合才发生在神经元中。最后，使用转基因的方法，我们发现，增加在体内的神经系统中的MFN 1的水平拯救突变MFN 2（R94 Q）表达小鼠的所有表型。这些数据表明，MFN 1/MFN 2比值是CMT 2A组织特异性的关键决定因素，并表明神经系统中MFN 1的增强是该疾病的可行治疗策略。
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondria! fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2(R94Q)-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.