Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
Department of Neurodegenerative Disease, UCL Queen Square, Institute of Neurology, University College London, London WC1N 3BG, UK.
Stem Cell Reports. 2021 May 11;16(5):1276-1289. doi: 10.1016/j.stemcr.2021.03.030. Epub 2021 Apr 22.
Sequestosome-1 (SQSTM1/p62) is involved in cellular processes such as autophagy and metabolic reprogramming. Mutations resulting in the loss of function of SQSTM1 lead to neurodegenerative diseases including frontotemporal dementia. The pathogenic mechanism that contributes to SQSTM1-related neurodegeneration has been linked to its role as an autophagy adaptor, but this is poorly understood, and its precise role in mitochondrial function and clearance remains to be clarified. Here, we assessed the importance of SQSTM1 in human induced pluripotent stem cell (iPSC)-derived cortical neurons through the knockout of SQSTM1. We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons. However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria. These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance.
自噬体相关蛋白 1（SQSTM1/p62）参与细胞自噬和代谢重编程等过程。导致 SQSTM1 功能丧失的突变会导致包括额颞叶痴呆在内的神经退行性疾病。导致 SQSTM1 相关神经退行性变的发病机制与其作为自噬衔接蛋白的作用有关，但这一点了解甚少，其在线粒体功能和清除中的确切作用仍有待阐明。在这里，我们通过敲除 SQSTM1 来评估 SQSTM1 在人诱导多能干细胞（iPSC）衍生的皮质神经元中的重要性。我们表明，SQSTM1 耗竭会导致 iPSC 衍生神经元中线粒体基因表达和功能以及自噬流的改变。然而，尽管 SQSTM1 对早期 PINK1 依赖性线粒体自噬过程（包括 PINK1 在去极化线粒体上的募集和泛素的磷酸化）有重大影响，但 SQSTM1 对于线粒体自噬并非必需。这些发现表明 SQSTM1 对于线粒体功能很重要，但对于清除作用并非必需。
