A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber's hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease of both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations.

中文翻译：

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MT-ND1中的m.3395A> G突变导致可变的病理表现。

在具有多种临床表型（如耳聋，糖尿病和小脑综合征）的几例患者中发现了一个非同义的mtDNA突变，m.3395A> G，将p.MT-ND1中的30位酪氨酸变为半胱氨酸。莱伯的遗传性视神经病变。尽管已经描述了这种突变，但尚未证明其致病性。在这里，首次发现它是分离的，可以进行一项研究以调查其致病性。为此，我们构建了杂交细胞系并进行了功能研究，以评估该突变对线粒体生物能学的可能影响。获得的结果表明，该突变引起线粒体呼吸链的重要功能障碍，由于p.MT-ND1数量的减少，复合物I的活性和数量均降低。然而，在携带突变的混合体中未发现亚复合物，表明复合物I装配的质量未受影响。此外，基于p.MT-ND1的晶体结构和文献中的数据，我们提出了p.MT-ND1降解机理的假设。我们的研究为线粒体疾病，尤其是MT-ND1突变的病理生理学提供了新的见解。