Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, QC, Canada.
Department of Chemistry, Biochemistry Division, Cairo University, Giza, Egypt.
Neurotox Res. 2022 Aug;40(4):1103-1114. doi: 10.1007/s12640-022-00475-w. Epub 2022 Jun 14.
An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, human cells have evolved sophisticated quality control mechanisms to identify and eliminate abnormal dysfunctional mitochondria. One pivotal mitochondrial quality control pathway is PINK1/Parkin-dependent mitophagy which mediates the selective removal of the dysfunctional mitochondria from the cell by autophagy. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial Ser/Thr kinase that was originally identified as a gene responsible for autosomal recessive early-onset Parkinson's disease (PD). Notably, upon failure of mitochondrial import, Parkin, another autosomal-recessive PD gene, is recruited to mitochondria and mediates the autophagic clearance of deregulated mitochondria. Importantly, recruitment of Parkin to damaged mitochondria hinges on the accumulation of PINK1 on the outer mitochondrial membrane (OMM). Normally, PINK1 is imported from the cytosol through the translocase of the outer membrane (TOM) complex, a large multimeric channel responsible for the import of most mitochondrial proteins. After import, PINK1 is rapidly degraded. Thus, at steady-state, PINK1 levels are kept low. However, upon mitochondrial import failure, PINK1 accumulates and forms a high-molecular weight > 700 kDa complex with TOM on the OMM. Thus, PINK1 functions as sensor, tagging dysfunctional mitochondria for Parkin-mediated mitophagy. Although much has been learned about the function of PINK1 in mitophagy, the biochemical and structural basis of negative regulation of PINK1 operation and functions is far from clear. Recent work unveiled new players as PTEN-l as negative regulator of PINK1 function. Herein, we review key aspects of mitophagy and PINK1/Parkin-mediated mitophagy with highlighting the role of negative regulation of PINK1 function and presenting some of the key future directions in PD cell biology.
线粒体面临的一个固有挑战是持续暴露于各种应激下，这增加了它们失调的可能性。作为回应，人类细胞已经进化出复杂的质量控制机制来识别和消除异常功能失调的线粒体。一条关键的线粒体质量控制途径是 PINK1/Parkin 依赖性的自噬体依赖的线粒体自噬，它通过自噬介导选择性地从细胞中去除功能失调的线粒体。PTEN 诱导的假定激酶 1（PINK1）是一种线粒体丝氨酸/苏氨酸激酶，最初被鉴定为一种负责常染色体隐性早发性帕金森病（PD）的基因。值得注意的是，在线粒体输入失败后，另一种常染色体隐性 PD 基因 Parkin 被招募到线粒体，并介导去调节线粒体的自噬清除。重要的是，Parkin 到受损线粒体的募集取决于 PINK1 在线粒体外膜（OMM）上的积累。正常情况下，PINK1 通过外膜转运体（TOM）复合物从细胞质中输入，TOM 复合物是一种大型多聚体通道，负责大多数线粒体蛋白的输入。输入后，PINK1 迅速降解。因此，在稳定状态下，PINK1 水平保持较低。然而，在线粒体输入失败时，PINK1 积累并与 OMM 上的 TOM 形成高分子量 > 700 kDa 复合物。因此，PINK1 作为传感器，标记功能失调的线粒体进行 Parkin 介导的线粒体自噬。尽管人们已经了解了 PINK1 在自噬体中的功能，但 PINK1 操作和功能的负调节的生化和结构基础还远不清楚。最近的工作揭示了新的参与者，如作为 PINK1 功能负调节剂的 PTEN-l。本文综述了自噬体和 PINK1/Parkin 介导的线粒体自噬的关键方面，强调了 PINK1 功能负调节的作用，并提出了 PD 细胞生物学的一些关键未来方向。
