Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy.
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy.
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DOI：
10.1186/s13024-021-00431-w
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发表时间：
2021-02-25
影响因子：
15.1
通讯作者：
Lenaers G
中科院分区：
文献类型：
--
作者：
Charif M;Wong YC;Kim S;Guichet A;Vignal C;Zanlonghi X;Bensaid P;Procaccio V;Bonneau D;Amati-Bonneau P;Reynier P;Krainc D;Lenaers G
遗传性视神经病变是最常见的线粒体疾病，可导致神经变性，包括视网膜神经节细胞的不可逆丧失、视神经变性和中枢视力丧失。重要的是，适当调节的线粒体动力学对于维持细胞稳态至关重要，并且由MIEF1（线粒体延伸因子1）进一步调节，该因子编码MID51（线粒体动力学蛋白51），MID51是一种线粒体外膜蛋白，作为调节线粒体裂变的适配蛋白。然而，MIEF1的显性突变以前并未与任何人类疾病联系起来。通过对参与线粒体动力学的基因进行靶向测序，我们报道了与疾病相关的MIEF1的第一个杂合变异，该变异导致一种不寻常的迟发性进行性视神经病变，其特征是初始周围视野丧失。与视神经病变相关的致病性MIEF1变异不会破坏MID51在线粒体外膜的定位或其寡聚化，而是在高空间和时间分辨率共聚焦显微镜实时成像研究中，与野生型MID51相比，显著破坏线粒体网络动力学。总之，我们的研究确定了MIEF1显性突变是视神经病变的一个原因，并进一步强调了适当调节线粒体动力学在神经变性中的重要作用。在线版本包含补充资料，网址为10.1186/s13024-021-00431-w。
Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration. The online version contains supplementary material available at 10.1186/s13024-021-00431-w.
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影响因子：
4.8
作者：
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