Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences - IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences - IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
Neurosci Lett. 2015 Jun 2;596:66-77. doi: 10.1016/j.neulet.2015.04.001. Epub 2015 Apr 3.
Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental role in mitochondrial transport and mutations in some of related encoding genes cause peripheral neuropathy (TUBB3, NEFL, HSPB1, HSPB8, HSPB3, DNAJB2). In this review, we address the abnormalities in mitochondrial dynamics and their role in determining CMT disease and related neuropathies.
周围神经由于轴突的巨大长度而具有特殊的能量需求，因此正确的线粒体功能和沿神经的分布是至关重要的。线粒体动力学是指细胞内线粒体大小、形状和位置的连续变化。涉及线粒体融合（线粒体融合蛋白 2，MFN2）、裂变（神经节苷脂诱导分化相关蛋白 1，GDAP1）和线粒体轴突运输的蛋白质突变引起的线粒体动力学异常通常表现为 Charcot-Marie-Tooth 病（CMT）表型。MFN2 突变通过改变线粒体融合和沿轴突微管系统的运输，导致 CMT 型 2A。CMT2A 是一种常染色体显性 CMT 型，在大多数情况下，其特征是发病早且病情严重。GDAP1 突变也改变了线粒体的裂变、融合和运输，与隐性脱髓鞘（CMT4A）和轴索性 CMT（AR-CMT2K）相关，以及不太常见的显性、较轻的轴索性 CMT（CMT2K）相关。OPA1（视神经萎缩 1）参与线粒体内膜的融合，其杂合突变导致早发性和进行性显性视神经萎缩，可能伴有其他神经症状，包括周围神经病。几种对轴突运输或形成轴突细胞骨架至关重要的蛋白质的突变导致周围神经病，即 CMT、遗传性远端运动神经病（dHMN）或遗传性感觉自主神经病（HSAN），以及遗传性痉挛性截瘫。事实上，线粒体运输直接或间接地涉及驱动蛋白超家族（KIF5A、KIF1A、KIF1B）的成分，负责向前运输，以及动力蛋白复合物和相关蛋白（DYNC1H1、动力蛋白激活蛋白、dynamin-2），参与逆行流动。微管、神经丝和热休克蛋白（HSPs）等伴侣蛋白也在线粒体运输中起着重要作用，一些相关编码基因的突变导致周围神经病（TUBB3、NEFL、HSPB1、HSPB8、HSPB3、DNAJB2）。在这篇综述中，我们讨论了线粒体动力学的异常及其在确定 CMT 疾病和相关神经病中的作用。
