Study discovers new pathology of mitochondrial lysosomal exocytosis in Parkinson's disease

Recently, Liu Xingguo's research group from Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences and Tian Mei's research group from Zhejiang University have made progress in the study of the mechanism of the clinical drug flunarizine that induces Parkinson's disease.
The study found that flunarizine induces mitochondrial Dysfunction and specifically reduces the number of mitochondria in the brain, induced cells to expel mitochondria out of the cell through the mitolysosome (mitolysosome), a novel organelle interacting structure in which lysosomes wrap mitochondria The total amount of mitochondria can lead to Parkinson's disease
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This work discovers a novel mitochondrial quality control mode independent of mitophagy in Parkinson's disease, and establishes a new compound-based method for the preparation of mitochondria-free cells without genetic manipulation
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Related research results are Mitolysosome exocytosis, a mitophagy-independent mitochondrial quality control in flunarizine-induced parkinsonism-like symptoms The title of "New Quality Control" was published in the form of a long article in Science Advances, a sub-journal of Science
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Parkinson's disease has plagued people's health and life, and it has become more severe with the aging society
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The PINK1-PARKIN-mediated mitochondrial phagocytosis by autophagosomes, which is related to the name Parkinson, is eliminated and is an important cause of Parkinson's disease
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In Parkinson's disease, whether there are other mitochondrial quality control pathways other than mitophagy to clear mitochondria is unclear
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Drug-induced parkinsonism is the second most common parkinsonism after primary parkinsonism
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Among the inducing drugs, Flunarizine and Cinarizine, as calcium channel inhibitors, are widely used in the treatment of vertigo, migraine, epilepsy, and peripheral vascular disease, and their induced Parkinson's disease accounts for higher specific gravity
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However, the mechanism of drug-induced Parkinson's disease is still unclear, which restricts the prevention and treatment of such diseases
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The study found that flunarizine can induce a Parkinson-like phenotype in mice, which is manifested in: decreased motor coordination in the rotarod test, decreased motor distance in the mining field test, and learning and memory in the water maze test.
decrease,
etc.

Pathological studies have shown decreased dopamine concentrations in the striatum
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Elevated glucose uptake in the brain was demonstrated using positron emission tomography and X-ray tomography (PET-CT), and western blotting confirmed a significant decrease in total mitochondrial volume in the brain but not in other organs
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In human neural precursor cells, flunarizine caused a dramatic drop in mitochondrial numbers, and almost all mitochondria disappeared after 3 days
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Where did the mitochondria go? Subsequent mechanistic studies found that flunarizine could induce mitochondria and lysosomes in neural cells to generate a new organelle structure, the mitolysosome, through a direct fusion
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Mitolysosome is a new English vocabulary created by research
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This process is independent of mitophagy, and the mitolysosome is subsequently effluxed in a VAMP2/STX4-dependent vesicle form, resulting in a decrease in the total mitochondrial volume in the cell
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The researchers conducted a genetic screen based on a genome-wide CRISPR/Cas9 knockout screen combined with a mito-GFP mitochondrial total marker, and discovered a series of new genes that regulate this process
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Mitochondrial exocytosis occurs in both pathophysiological settings, such as neurons and astrocytes, which can release mitochondria to circulate and transfer in the brain, so the discovery of a novel lysosome-dependent mitochondrial exocytosis pathway may have broad physiological pathological significance
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Flunarizine treatment produces a mammalian cell model with complete mitochondrial depletion
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The research has been tried and successful in a variety of human and mouse cells, so that eukaryotic cells completely free of mitochondria can be obtained
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This new cell model has broad application prospects.
It can remove mitochondria from patient cells with mitochondrial DNA mutations, and combine mitochondrial delivery technology to correct mitochondrial genetic defects; it can also directly study new mitochondrial functions through a new model without mitochondrial interference.

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The research work is supported by the National Key R&D Program, Chinese Academy of Sciences, National Natural Science Foundation of China, Guangdong Province and Guangzhou City
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A new pathway for mitochondrial lysosome exocytosis in Parkinson's disease Source: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences