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Abnormal accumulation of α-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how α-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant α-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission, but also restores the mitochondrial dysfunction and cell death in α-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.p38MAPK directly interacts with and phosphorylates the DRP1 at serine 616 site.p38MAPK activation leads to mitochondrial dysfunction and dopaminergic neuron death by disrupting mitochondrial homeostasis.p38MAPK-DRP1 signal pathway may be a viable therapeutic target of PD via maintenance of mitochondrial homeostasis.