Laboratory for Parkinson Research, Department of Neurosciences, Leuven, Belgium.
Department of Neurosciences, KU Leuven, Leuven, Belgium.
Elife. 2018 May 29;7:e35878. doi: 10.7554/eLife.35878.
Mutations in the genes for PINK1 and parkin cause Parkinson's disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM), we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins. Mitophagy increases with aging, and this age-dependent rise is abrogated by PINK1 or parkin deficiency. Knockdown of the homologues of the deubiquitinases USP15 and, to a lesser extent, USP30, rescues mitophagy in the parkin-deficient flies. These data demonstrate a crucial role for parkin and PINK1 in age-dependent mitophagy in in vivo.
PINK1 和 parkin 基因突变会导致帕金森病。在培养细胞中，PINK1 和 parkin 合作进行受损线粒体的选择性自噬降解（mitophagy）。然而，它们在体内mitophagy 中的作用的证据仍然很少。在这里，我们生成了一个表达 mitophagy 探针 mt-Keima 的模型。使用活细胞 mt-Keima 成像和相关的光和电子显微镜（CLEM），我们表明mitophagy 发生在体内的肌肉细胞和多巴胺能神经元中，即使没有外源性线粒体毒素也是如此。mitophagy 随年龄增长而增加，而 PINK1 或 parkin 缺乏会消除这种年龄依赖性增加。去泛素化酶 USP15 的同源物的敲低，在较小程度上，USP30 的敲低，可挽救 parkin 缺陷果蝇中的 mitophagy。这些数据表明 parkin 和 PINK1 在体内与年龄相关的 mitophagy 中起着至关重要的作用。
