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首页> 外文期刊>Biochemical Genetics >DNM1L Variant Alters Baseline Mitochondrial Function and Response to Stress in a Patient with Severe Neurological Dysfunction
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DNM1L Variant Alters Baseline Mitochondrial Function and Response to Stress in a Patient with Severe Neurological Dysfunction

机译：DNM1L变体改变基线线粒体功能，并对具有严重神经功能障碍的患者的应激响应

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Abstract Mitochondria play vital roles in brain development and neuronal activity, and mitochondrial dynamics (fission and fusion) maintain organelle function through the removal of damaged components. Dynamin-like protein-1 (DRP-1), encoded by DNM1L , is an evolutionarily conserved GTPase that mediates mitochondrial fission by surrounding the scission site in concentric ring-like structures via self-oligomerization, followed by GTPase-dependant constriction. Here, we describe the clinical characteristics and cellular phenotype of a patient with severe neurological dysfunction, possessing a homozygous DNM1L variant c.305C>T (p.T115M) in the GTPase domain. For comparative analysis, we also describe a previously identified heterozygous variant demonstrating a rapidly fatal neurocognitive phenotype (c.261dup/c.385:386del, p.W88M*9/E129K*6). Using patient-generated fibroblasts, we demonstrated both DNM1L variants undergo adverse alterations to mitochondrial structure and function, including impaired mitochondrial fission, reduced membrane potential, and lower oxidative capacity including an increased cellular level of reactive oxygen species (ROS) and dsDNA breaks. Mutation of DNM1L was also associated with impaired responses to oxidative stress, as treatment with hydrogen peroxide dramatically increased cellular ROS, with minimal exacerbation of already impaired mitochondrial function. Taken together, our observations indicate that homozygous p.T115M variant of DNM1L produces a neurological and neurodevelopmental phenotype, consistent with impaired mitochondrial architecture and function, through a diminished ability to oligomerize, which was most prevalent under oxidative stress.
机译：摘要线粒体在大脑发育和神经元活动中发挥重要作用，线粒体动力学（裂变和融合）通过去除受损部件来保持细胞石功能。 Dynam样蛋白-1（DRP-1）由DNM1L编码，是一种进化保守的GTP酶，其通过通过自寡聚化通过自寡聚化围绕同心环状结构围绕着裂殖部位来介导线粒体裂变，然后进行GTP酶依赖性收缩。在这里，我们描述了具有严重神经功能功能障碍的患者的临床特征和细胞表型，在GTP酶结构域中具有纯合DNM1L变体C.305C> T（P.T115M）。对于比较分析，我们还描述了先前鉴定的杂合变形，证明了迅速致命的神经过度认知表型（C.261Dup / C.385：386Del，P.W8M * 9 / E129K * 6）。使用患者产生的成纤维细胞，我们证明了DNM1L变体两者都经过对线粒体结构和功能的不利改变，包括受损的线粒体裂变，降低的膜电位和较低的氧化能力，包括增加的反应性氧物质（ROS）和DSDNA断裂的细胞水平增加。 DNM11的突变也与对氧化应激的反应有损害，因为用过氧化氢的处理显着增加了细胞ROS，并且对已经受损的线粒体功能的最小加剧了。我们的观察结果表明DNM1L的纯合P.T115M变体产生神经和神经发育的表型，其通过减少氧化胁迫下最普遍的抗体化的线粒体建筑和功能，这是一种神经系统和神经发育的表型。

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