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The conserved dynamin-like GTPase, Mitofusin2 (MFN2)\/mitochondrial assembly regulatory factor (Marf), plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2\/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, is not clearly understood. Here, we identified a novel interaction between MFN2\/Marf and microtubule affinity-regulating kinase 4 (MARK4)\/PAR-1. In the<jats:italic>Drosophila<\/jats:italic>larval neuromuscular junction, muscle-specific overexpression of MFN2\/Marf decreased the number of synaptic boutons, and the loss of MARK4\/PAR-1 alleviated the synaptic defects of MFN2\/Marf overexpression. Downregulation of MARK4\/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2\/Marf overexpression in the<jats:italic>Drosophila<\/jats:italic>muscles as well as in the cultured cells. In addition, knockdown of MARK4\/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2\/Marf overexpression in mammalian cells. Together, our results indicate that the interaction between MFN2\/Marf and MARK4\/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.<\/jats:p>","DOI":"10.1523\/eneuro.0409-22.2023","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T17:50:11Z","timestamp":1691430611000},"page":"ENEURO.0409-22.2023","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Interaction between MFN2\/Marf and MARK4\/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial 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