Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease.
Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease.
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DOI：
10.1038/srep44373
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发表时间：
2017-03-10
影响因子：
4.6
通讯作者：
Sue CM
中科院分区：
文献类型：
--
作者：
Koentjoro B;Park JS;Sue CM
帕金森氏病(PD)的神经保护性治疗需要治疗靶点。有丝分裂是对功能障碍的线粒体的选择性自噬消除，对于维持线粒体的完整性是必不可少的，并且主要由PINK1/Parkin介导的途径调节。Parkin和PINK1功能突变缺失导致功能障碍的线粒体积聚，导致黑质神经变性和高外显率的早发性帕金森病。我们之前发现了一例无症状的纯合子帕金氏突变携带者，尽管失去了功能性帕金氏病，但在她80岁时仍未发展为帕金森氏病。在这里，我们发现了一种假定的机制，可以保护她免受帕金森病的伤害。与帕金森病患者来源的细胞不同，无症状的载体细胞表现出线粒体功能的保留和线粒体受体Nip3样蛋白X(NIX)介导的有丝分裂。NIX介导的丝裂原吞噬不受PINK1基因敲除的影响。Nix的遗传和药物诱导都能恢复PINK1和Parkin相关的PD患者细胞系的有丝分裂，证实了其在缺乏PINK1/Parkin介导的途径的情况下诱导有丝分裂的能力。此外，NIX的过度表达提高了这些患者细胞中线粒体的ATP产量。我们的结果表明，NIX可以作为一种替代的线粒体吞噬介质来维持线粒体的更新，这表明NIX是PINK1/Parkin相关PD神经保护治疗的一个有前景的靶点。
Therapeutic targets are needed to develop neuroprotective treatments for Parkinson’s disease (PD). Mitophagy, the selective autophagic elimination of dysfunctional mitochondria, is essential for the maintenance of mitochondrial integrity and is predominantly regulated by the PINK1/Parkin-mediated pathway. Loss of function mutations in Parkin and PINK1 cause an accumulation of dysfunctional mitochondria, leading to nigral neurodegeneration and early-onset PD with a high penetrance rate. We previously identified an asymptomatic homozygous Parkin mutation carrier who had not developed PD by her eighth decade despite the loss of functional Parkin. Here we discover a putative mechanism that protects her against PD. In contrast to Parkin-related PD patient-derived cells, the asymptomatic carrier cells show preserved mitochondrial function and mitophagy which is mediated by mitochondrial receptor Nip3-like protein X (Nix). Nix-mediated mitophagy was not affected by PINK1 knockdown. Both genetic and pharmacological induction of Nix restores mitophagy in PINK1- and Parkin-related PD patient cell lines, confirming its ability to induce mitophagy in the absence of PINK1/Parkin-mediated pathway. Moreover, Nix over-expression improves mitochondrial ATP production in these patient cells. Our results demonstrate that Nix can serve as an alternative mediator of mitophagy to maintain mitochondrial turnover, identifying Nix as a promising target for neuroprotective treatment in PINK1/Parkin-related PD.