Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by a gradual loss of a specific group of dopaminergic neurons in the substantia nigra. Importantly, current treatments only address the symptoms of PD, yet not the underlying molecular causes. Concomitantly, the function of genes that cause inherited forms of PD point to mitochondrial dysfunction as a major contributor in the etiology of PD. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses including high levels of reactive oxygen species and protein misfolding, which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to identify, repair and/or eliminate abnormal dysfunctional mitochondria. One such mechanism is mitophagy, a process which involves PTEN-induced putative kinase 1 (PINK1), a mitochondrial Ser/Thr kinase and Parkin, an E3 ubiquitin ligase, each encoded by genes responsible for early-onset autosomal recessive familial PD. Over 100 loss-of-function mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been reported to cause autosomal recessive early-onset PD. PINK1 acts upstream of Parkin and is essential for the mitochondrial localization and activation of Parkin. Upon mitochondrial damage, PINK1 builds up on the outer mitochondrial membrane (OMM) and mediates the activation of Parkin. Activated Parkin then ubiquitinates numerous OMM proteins, eliciting mitochondrial autophagy (mitophagy). As a result, damaged mitochondrial components can be selectively eliminated. Thus, PINK1 acts a sensor of damage via fine-tuning of its levels on mitochondria, where it activates Parkin to orchestrate the clearance of unhealthy mitochondria. Previous work has unveiled that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of PINK1, and thus fine-tune PINK1-dependent mitochondrial quality control pathway. Herein, we briefly discuss the interconnection between N-end rule degradation pathways and mitophagy in the context of N-degron mediated degradation of mitochondrial kinase PINK1 and highlight some of the future prospects.

帕金森氏病（PD）是一种进行性神经退行性疾病，其特征是黑质中特定组的多巴胺能神经元逐渐丢失。重要的是，目前的治疗方法仅能解决PD的症状，而不能解决潜在的分子原因。伴随地，引起PD的遗传形式的基因的功能表明线粒体功能障碍是PD病因的主要贡献者。线粒体面临的固有挑战是持续暴露于各种压力下，包括高水平的活性氧和蛋白质错误折叠，这增加了它们失调的可能性。作为响应，真核细胞已进化出复杂的质量控制机制，以识别，修复和/或消除异常的线粒体功能异常。线粒体就是其中一种机制，该过程涉及PTEN诱导的假定激酶1（PINK1），线粒体Ser / Thr激酶和E3泛素连接酶Parkin，它们均由负责早发型常染色体隐性家族性PD的基因编码。据报道，PTEN诱导的假定激酶1（PINK1）基因中的100多个功能丧失突变可导致常染色体隐性遗传性早发性PD。PINK1在Parkin的上游起作用，对于线粒体的定位和Parkin的激活至关重要。线粒体损伤后，PINK1会在线粒体外膜（OMM）上积聚并介导Parkin的激活。然后，活化的帕金蛋白泛素化许多OMM蛋白，引起线粒体自噬（有丝分裂）。结果，可以选择性地消除受损的线粒体成分。从而，PINK1通过微调线粒体上的水平来发挥损伤传感器的作用，并在其中激活Parkin来协调清除不健康的线粒体的过程。先前的工作表明Arg-N端法则降解途径（Arg- N- degron途径）介导PINK1的降解，因此可以微调PINK1依赖性线粒体质量控制途径。在本文中，我们简要讨论了在N -degron介导的线粒体激酶PINK1降解的背景下N端规则降解途径与线粒体之间的相互关系，并强调了一些未来前景。