PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling
PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling
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DOI：
10.1126/science.1249161
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发表时间：
2014-04-11
期刊：
影响因子：
56.9
通讯作者：
De Strooper, Bart
中科院分区：
文献类型：
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作者：
Morais, Vanessa A.;Haddad, Dominik;De Strooper, Bart
在静息条件下，PINK 1敲除细胞和来自PINK 1突变患者的细胞显示线粒体复合物I还原活性的丧失，导致线粒体膜电位降低。分析Pink 1（-/-）小鼠肝脏和大脑中复合物I的磷酸化蛋白质组，我们发现复合物I亚基NdufA 10中丝氨酸-250磷酸化的特异性丢失。丝氨酸-250的磷酸化是复合物I还原泛醌所必需的。拟磷酸化NdufA 10逆转了小鼠敲除细胞中的Pink 1缺陷，并挽救了粉红色（B 9）缺失突变果蝇中的线粒体去极化和突触传递缺陷。在来自PINK 1患者的细胞中，复合物I缺陷和三磷酸腺苷合成也被拯救。因此，这种进化保守的途径可能有助于致病级联反应，最终导致PINK 1突变患者患帕金森病。
Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations.