UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging- related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and ALS. In this study, we show that after Parkin- dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly- ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin- mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）与额颞叶痴呆（frontotemporal dementia, FTD）是两类与衰老相关的神经退行性疾病，二者具备多项共同核心病理特征，包括致病性蛋白聚集、线粒体功能异常及自噬功能受损。泛素-蛋白酶体系统（ubiquitin-proteasome system, UPS）中的穿梭蛋白泛素蛋白2（ubiquilin 2, UBQLN2）发生突变可引发ALS/FTD，但UBQLN2介导的致病机制目前仍不明确。近期研究表明，线粒体自噬（mitophagy）——一种对线粒体质量控制至关重要的选择性自噬形式——与阿尔茨海默病、帕金森病及ALS等神经退行性疾病密切相关。本研究发现，在受损线粒体经Parkin介导的泛素化修饰后，UBQLN2可通过其UBA结构域（UBA domain）被招募至多泛素化线粒体表面。UBQLN2与分子伴侣HSP70协同作用，促进泛素-蛋白酶体系统对线粒体外膜（outer mitochondrial membrane, OMM）蛋白的降解。由此引发的线粒体外膜破裂，会触发自噬体对线粒体内膜受体PHB2的识别。在线粒体损伤条件下，UBQLN2是Parkin介导的线粒体自噬及神经元存活所必需的；而UBQLN2上的ALS/FTD致病突变会损害原代培养神经元中的线粒体自噬功能。综上，本研究结果将功能异常的线粒体自噬与UBQLN2介导的神经退行性变联系起来。