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.