Bao Feixiang, Zhou Lingyan, Zhou Rui, Huang Qiaoying, Chen Junguo, Zeng Sheng, Wu Yi, Yang Liang, Qian Shufang, Wang Mengfei, He Xueying, Liang Shan, Qi Juntao, Xiang Ge, Long Qi, Guo Jingyi, Ying Zhongfu, Zhou Yanshuang, Zhao Qiuge, Zhang Jiwei, Zhang Di, Sun Wei, Gao Mi, Wu Hao, Zhao Yifan, Nie Jinfu, Li Min, Chen Quan, Chen Jiekai, Zhang Xiao, Pan Guangjin, Zhang Hong, Li Mingtao, Tian Mei, Liu Xingguo
CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.
Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Guangzhou, China.
Sci Adv. 2022 Apr 15;8(15):eabk2376. doi: 10.1126/sciadv.abk2376. Epub 2022 Apr 13.
Mitochondrial quality control plays an important role in maintaining mitochondrial homeostasis and function. Disruption of mitochondrial quality control degrades brain function. We found that flunarizine (FNZ), a drug whose chronic use causes parkinsonism, led to a parkinsonism-like motor dysfunction in mice. FNZ induced mitochondrial dysfunction and decreased mitochondrial mass specifically in the brain. FNZ decreased mitochondrial content in both neurons and astrocytes, without affecting the number of nigral dopaminergic neurons. In human neural progenitor cells, FNZ also induced mitochondrial depletion. Mechanistically, independent of ATG5- or RAB9-mediated mitophagy, mitochondria were engulfed by lysosomes, followed by a vesicle-associated membrane protein 2- and syntaxin-4-dependent extracellular secretion. A genome-wide CRISPR knockout screen identified genes required for FNZ-induced mitochondrial elimination. These results reveal not only a previously unidentified lysosome-associated exocytosis process of mitochondrial quality control that may participate in the FNZ-induced parkinsonism but also a drug-based method for generating mitochondria-depleted mammal cells.
线粒体质量控制在维持线粒体稳态和功能方面发挥着重要作用。线粒体质量控制的破坏会损害脑功能。我们发现，长期使用会导致帕金森症的药物氟桂利嗪（FNZ）在小鼠中引发了类似帕金森症的运动功能障碍。FNZ 诱导了线粒体功能障碍，并特异性地减少了脑中的线粒体质量。FNZ 降低了神经元和星形胶质细胞中的线粒体含量，而不影响黑质多巴胺能神经元的数量。在人类神经祖细胞中，FNZ 也诱导了线粒体耗竭。从机制上讲，在线粒体自噬不依赖于 ATG5 或 RAB9 介导的情况下，线粒体被溶酶体吞噬，随后通过囊泡相关膜蛋白 2 和 syntaxin-4 依赖的细胞外分泌过程排出。全基因组 CRISPR 敲除筛选确定了 FNZ 诱导线粒体清除所需的基因。这些结果不仅揭示了一种先前未被识别的线粒体质量控制中与溶酶体相关的胞吐过程，该过程可能参与 FNZ 诱导的帕金森症，还揭示了一种基于药物的方法来生成线粒体耗竭的哺乳动物细胞。
