A Novel Interaction between MFN2/Marf and MARK4/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial Dysfunction

Abstract

(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 identi-fied a novel interaction between MFN2/Marf and microtubule affinity-regulating kinase 4 (MARK4)/PAR-1. In the Drosophila 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 Drosophila muscles as well as in the cultured cells. In addition, knock-down of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overex-pression 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 dysregula-tion may be implicated in neurologic pathogenesis.Significance StatementWe identified a novel interaction between MFN2/Marf and kinase MARK4/PAR-1 in Drosophila and mamma-lian cells. The MFN2/Marf and MARK4/PAR-1 interaction was critical for maintaining the synaptic structure of neuromuscular junctions in Drosophila. In addition, we found that concomitant knockdown of MARK4/ PAR-1 could rescue the mitochondrial hyperfusion and aberrant respiratory function caused by MFN2/Marf overexpression. Our study provides new insights into the link between mitochondrial defects and neurode-generation, which makes a significant contribution to the understanding of neurologic pathogenesis and therapeutic development.