2. Academic Validation
  3. Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms

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

  • Sci Adv. 2022 Apr 15;8(15):eabk2376. doi: 10.1126/sciadv.abk2376.
Feixiang Bao 1 2,  Lingyan Zhou 1 2,  Rui Zhou 3,  Qiaoying Huang 4,  Junguo Chen 4,  Sheng Zeng 1 2,  Yi Wu 1 2,  Liang Yang 1 2,  Shufang Qian 3,  Mengfei Wang 1 2,  Xueying He 1 2,  Shan Liang 1 2,  Juntao Qi 1 2,  Ge Xiang 1 2 5,  Qi Long 1 2,  Jingyi Guo 1 2,  Zhongfu Ying 1 2 5,  Yanshuang Zhou 1 2,  Qiuge Zhao 6,  Jiwei Zhang 7,  Di Zhang 1 2,  Wei Sun 1 2,  Mi Gao 1 2,  Hao Wu 1 2,  Yifan Zhao 1 2,  Jinfu Nie 1 2,  Min Li 8,  Quan Chen 9,  Jiekai Chen 1 2,  Xiao Zhang 1 2,  Guangjin Pan 1 2,  Hong Zhang 3,  Mingtao Li 4,  Mei Tian 3,  Xingguo Liu 1 2 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Brain Function and Disease, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 GMU-GIBH Joint School of Life Sciences, Center of Reproductive Medicine, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 6 The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 7 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
  • 8 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
  • 9 College of Life Sciences, Nankai University, Tianjin, China.
  • 10 Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, SAR China.
PMID: 35417232 DOI: 10.1126/sciadv.abk2376
Abstract

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.

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