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.

中文翻译：

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MIEF1 的显性突变影响线粒体动力学并导致单一的迟发性视神经病变


遗传性视神经病是最常见的线粒体疾病，可导致神经变性，包括不可逆的视网膜神经节细胞损失、视神经变性和中央视力丧失。重要的是，正确调节线粒体动力学对于维持细胞稳态至关重要，并受到 MIEF1（线粒体伸长因子 1）的进一步调节，MIEF1 编码 MID51（线粒体动力学蛋白 51），MID51 是一种线粒体外膜蛋白，可作为调节线粒体的衔接蛋白。裂变。然而，MIEF1 的显性突变此前并未与任何人类疾病相关。通过对参与线粒体动力学的基因进行靶向测序，我们报告了 MIEF1 中与疾病相关的第一个杂合变异，这种变异会导致一种不寻常的迟发性进行性视神经病，其特征是最初丧失周围视野。与视神经病变相关的致病性 MIEF1 变异不会破坏 MID51 定位到线粒体外膜或其寡聚化，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，显着破坏线粒体网络动态。总之，我们的研究确定了显性 MIEF1 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。