Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms

• DOI: 10.1126/sciadv.abk2376
• Publication Date: 2022-04-13T17:52:52Z
• Authors: Feixiang Bao; Lingyan Zhou; Rui Zhou; Qiaoying Huang; Junguo Chen; Sheng Zeng; Yi Wu; Liang Yang; Shufang Qian; Mengfei Wang; Xueying He; Shan Liang; Juntao Qi; Ge Xiang; Qi Long; Jingyi Guo; Zhongfu Ying; Yanshuang Zhou; Qiuge Zhao; Jiwei Zhang; Di Zhang; Wei Sun; Mi Gao; Hao Wu; Yifan Zhao; Jinfu Nie; Min Li; Quan Chen; Jiekai Chen; Xiao Zhang; Guangjin Pan; Hong Zhang; Mingtao Li; Mei Tian; Xingguo Liu
• Keywords: PINK1; MPTP

Mitochondrial quality control plays an important role in maintaining mitochondrial homeostasis and function. Disruption of degrades brain We found that flunarizine (FNZ), a drug whose chronic use causes parkinsonism, led to parkinsonism-like motor dysfunction mice. FNZ induced decreased mass specifically the brain. content both neurons astrocytes, without affecting number nigral dopaminergic neurons. In human neural progenitor cells, also depletion. Mechanistically, independent ATG5- or RAB9-mediated mitophagy, mitochondria were engulfed by lysosomes, followed vesicle-associated membrane protein 2- syntaxin-4-dependent extracellular secretion. A genome-wide CRISPR knockout screen identified genes required for FNZ-induced elimination. These results reveal not only previously unidentified lysosome-associated exocytosis process may participate parkinsonism but drug-based method generating mitochondria-depleted mammal cells.