Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.
Cell Death Dis. 2019 Jul 22;10(8):563. doi: 10.1038/s41419-019-1752-5.
Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
唐氏综合征（DS）是一种由 21 号染色体三体引起的复杂遗传疾病，与线粒体功能障碍有关，导致受损线粒体的积累。在这里，我们报告说，自噬是一种清除受损线粒体的选择性自噬形式，在源自 DS 个体的原代人成纤维细胞中存在缺陷，导致受损线粒体的积累，随之而来的是氧化应激的增加。我们确定了这种自噬缺陷的两个分子基础：PINK1/PARKIN 损伤和巨自噬的异常抑制。首先，强烈下调的 PARKIN 和自噬衔接蛋白 SQSTM1/p62 延迟 PINK1 的激活，从而在 CCCP 或抗霉素 A 加寡霉素引起的线粒体去极化后损害自噬诱导。其次，mTOR 被强烈地过度激活，这会全局抑制巨自噬的诱导以及自噬体形成所必需的蛋白质（如 ATG7、ATG3 和 FOXO1）的转录表达。值得注意的是，使用 AZD8055（AZD）抑制 mTOR 复合物 1（mTORC1）和复合物 2（mTORC2）可恢复自噬流、PARKIN/PINK 启动的自噬和通过自噬清除受损线粒体。这些结果表明抑制 mTORC1-mTORC2 是唐氏综合征有前途的治疗策略。
