Homozygous YME1L1 Mutation Causes Mitochondriopathy with Optic Atrophy and Mitochondrial Network Fragmentation
Homozygous YME1L1 Mutation Causes Mitochondriopathy with Optic Atrophy and Mitochondrial Network Fragmentation
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DOI：
10.7554/elife.16078
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发表时间：
2016-08-06
期刊：
影响因子：
7.7
通讯作者：
Kaindl, Angela M.
中科院分区：
文献类型：
--
作者：
Hartmann, Bianca;Wai, Timothy;Kaindl, Angela M.
线粒体病在临床上通常表现为主要是高能量消耗器官的多系统疾病。线粒体蛋白的组装、周转和监视对于线粒体功能是必不可少的，并且是金属蛋白酶AAA家族成员的关键任务。我们确定了一个纯合突变的核编码的线粒体逃逸1样1基因YME1L1，AAA蛋白酶家族的成员，作为一种新的arrhopathy在沙特阿拉伯血统的血缘家系的原因。位于线粒体前序列中高度保守区域的纯合错义突变抑制线粒体加工肽酶对YME1L1的切割，其最终导致YME1L1前体蛋白的快速降解。受损的YME1L1功能由于OPA1的异常加工而导致增殖缺陷和线粒体网络断裂。我们的研究结果确定了YME1L1突变是导致视神经萎缩的视网膜病变的原因，突出了YME1L1对人类线粒体功能的重要性。
Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.