Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role in the pathogenesis of Parkinson's disease (PD). PARKIN regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. Defects in mitophagy have been hypothesized to play a predominant role in the loss of dopamine (DA) neurons in PD. Here, we show that although there are defects in mitophagy in human DA neurons lacking PARKIN, the mitochondrial deficits are primarily due to defects in mitochondrial biogenesis that are driven by the upregulation of PARIS and the subsequent downregulation of PGC-1α. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without affecting the deficits in mitophagy. These results highlight the importance mitochondrial biogenesis versus mitophagy in the pathogenesis of PD due to inactivation or loss of PARKIN in human DA neurons.

PARKIN（一种 E3 泛素连接酶）的突变和活性丧失在帕金森病 (PD) 的发病机制中发挥着重要作用。 PARKIN 调节线粒体质量控制的许多方面，包括线粒体自噬（mitophagy）和线粒体生物合成。据推测，线粒体自噬缺陷在 PD 中多巴胺 (DA) 神经元的丧失中起主要作用。在这里，我们发现，虽然缺乏PARKIN的人类 DA 神经元存在线粒体自噬缺陷，但线粒体缺陷主要是由于 PARIS 上调和随后 PGC-1α 下调驱动的线粒体生物合成缺陷所致。 PARIS 的 CRISPR/Cas9 敲除完全恢复了线粒体生物发生缺陷和线粒体功能，而不影响线粒体自噬的缺陷。这些结果强调了线粒体生物发生与线粒体自噬在由于人类 DA 神经元中 PARKIN 失活或缺失而导致的 PD 发病机制中的重要性。