Impairment of PINK 1/parkin‐mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD ). We here demonstrate that PINK 1 directly phosphorylates Drp1 on S616. Drp1^S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK 1, but unaffected by parkin inactivation. PINK 1‐mediated mitochondrial fission is Drp1^S616 phosphorylation dependent. Overexpression of either wild‐type Drp1 or of the phosphomimetic mutant Drp1^S616D, but not a dephosphorylation‐mimic mutant Drp1^S616A, rescues PINK 1 deficiency‐associated phenotypes in Drosophila . Moreover, Drp1 restores PINK 1‐dependent mitochondrial fission in ATG 5‐null cells and ATG 7‐null Drosophila . Reduced Drp1^S616 phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK 1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK 1 and a novel mechanism how PINK 1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK 1‐mediated Drp1^S616 phosphorylation with the pathogenesis of both familial and sporadic PD .

中文翻译：

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PINK1 磷酸化 Drp1S616 以调节不依赖线粒体自噬的线粒体动力学。

目前认为 PINK 1/parkin 介导的线粒体自噬受损是帕金森病 (PD) 线粒体异常的分子基础。我们在此证明 PINK 1 直接磷酸化 S616 上的 Drp1。在 PINK 1 缺陷的细胞和小鼠组织中，Drp1 ^{S616磷酸化显着降低，但不受 Parkin 失活的影响。}PINK 1 介导的线粒体分裂依赖于 Drp1 ^S616磷酸化。野生型 Drp1 或磷酸模拟突变体 Drp1 ^S616D的过表达（但不是去磷酸化模拟突变体 Drp1 ^{S616A ）可以挽救}果蝇中与 PINK 1 缺陷相关的表型。此外，Drp1 可恢复 ATG 5 缺失细胞和 ATG 7 缺失果蝇中 PINK 1 依赖性线粒体分裂。在 4 名携带 PINK 1 突变的 PD 患者以及 7 名散发性 PD 病例中的 4 名的成纤维细胞中检测到Drp1 ^{S616磷酸化降低。}综上所述，我们确定了 Drp1 是 PINK 1 的底物，以及 PINK 1 独立于 Parkin 和自噬调节线粒体裂变的新机制。我们的结果进一步将 PINK 1 介导的 Drp1 ^S616磷酸化受损与家族性和散发性 PD 的发病机制联系起来。