Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration.
Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration.
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DOI：
10.1523/jneurosci.6338-11.2012
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发表时间：
2012-03-21
期刊：
影响因子：
--
通讯作者：
Baloh RH
中科院分区：
文献类型：
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作者：
Misko AL;Sasaki Y;Tuck E;Milbrandt J;Baloh RH
线粒体动力学（裂变、融合和运动）的改变与许多神经退行性疾病有关，从罕见的遗传性疾病（如腓骨肌萎缩症）到常见疾病（如阿尔茨海默病）。然而，线粒体动力学改变与神经退行性变之间的关系尚不完全清楚。在这里，我们表明，与疾病相关的 MFN2 蛋白抑制线粒体融合和运输，并产生节段性轴突变性而不导致细胞体死亡的典型特征，包括神经丝填充肿胀、钙稳态丧失和活性氧积累。相比之下，Opa1 的耗竭抑制了线粒体融合，同时减少了运输，并且不会诱导轴突变性。突变 MFN2 蛋白诱导的轴突变性与轴突内线粒体正确定位的破坏相关，而不是整体线粒体运动的丧失或整体线粒体功能障碍。我们还发现，增加 MFN1 的表达可以挽救 MFN2 突变体引起的轴突变性，这表明可能是腓骨肌萎缩症的治疗策略。这些实验提供的证据表明，线粒体感知能量需求并在轴突内正确定位的能力是维持轴突完整性的关键，并且可能是轴突运输中断导致神经退行性变的常见途径。
Alterations in mitochondrial dynamics (fission, fusion and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders such as Charcot-Marie-Tooth disease, to common conditions including Alzheimer’s disease. However, the relationship between altered mitochondrial dynamics and neurodegeneration is incompletely understood. Here we show that disease associated MFN2 proteins suppressed both mitochondrial fusion and transport, and produced classic features of segmental axonal degeneration without cell body death, including neurofilament filled swellings, loss of calcium homeostasis, and accumulation of reactive oxygen species. By contrast, depletion of Opa1 suppressed mitochondrial fusion while sparing transport, and did not induce axonal degeneration. Axon degeneration induced by mutant MFN2 proteins correlated with the disruption of the proper mitochondrial positioning within axons, rather than loss of overall mitochondrial movement, or global mitochondrial dysfunction. We also found that augmenting expression of MFN1 rescued the axonal degeneration caused by MFN2 mutants, suggesting a possible therapeutic strategy for Charcot-Marie-Tooth disease. These experiments provide evidence that the ability of mitochondria to sense energy requirements and localize properly within axons is key to maintaining axonal integrity, and may be a common pathway by which disruptions in axonal transport contribute to neurodegeneration.