title: DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease.
abstract: Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) can be modeled by the administration of the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+) ). Because abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this study, we investigated the effect of MPP(+) on mitochondrial dynamics and assessed temporal and causal relationship with other toxic effects induced by MPP(+) in neuronal cells. In SH-SY5Y cells, MPP(+) causes a rapid increase in mitochondrial fragmentation followed by a second wave of increase in mitochondrial fragmentation, along with increased DLP1 expression and mitochondrial translocation. Genetic inactivation of DLP1 completely blocks MPP(+) -induced mitochondrial fragmentation. Notably, this approach partially rescues MPP(+) -induced decline in ATP levels and ATP/ADP ratio and increased [Ca(2+) ](i) and almost completely prevents increased reactive oxygen species production, loss of mitochondrial membrane potential, enhanced autophagy and cell death, suggesting that mitochondria fragmentation is an upstream event that mediates MPP(+) -induced toxicity. On the other hand, thiol antioxidant N-acetylcysteine or glutamate receptor antagonist D-AP5 also partially alleviates MPP(+) -induced mitochondrial fragmentation, suggesting a vicious spiral of events contributes to MPP(+) -induced toxicity. We further validated our findings in primary rat midbrain dopaminergic neurons that 0.5 μm MPP(+) induced mitochondrial fragmentation only in tyrosine hydroxylase (TH)-positive dopaminergic neurons in a similar pattern to that in SH-SY5Y cells but had no effects on these mitochondrial parameters in TH-negative neurons. Overall, these findings suggest that DLP1-dependent mitochondrial fragmentation plays a crucial role in mediating MPP(+) -induced mitochondria abnormalities and cellular dysfunction and may represent a novel therapeutic target for PD.
authors: Department of Pathology, Case Western Reserve University, 2103 Connell Road, Cleveland, OH 44106, USA.
authors: Xinglong
authors: X
authors: Wang
authors: Bo
authors: B
authors: Su
authors: Wanhong
authors: W
authors: Liu
authors: Xiaohua
authors: X
authors: He
authors: Yuan
authors: Y
authors: Gao
authors: Rudy J
authors: RJ
authors: Castellani
authors: George
authors: G
authors: Perry
authors: Mark A
authors: MA
authors: Smith
authors: Xiongwei
authors: X
authors: Zhu
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