DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease

作者：Wang Xinglong; Su Bo; Liu Wanhong; He Xiaohua; Gao Yuan; Castellani Rudy J; Perry George; Smith Mark A; Zhu Xiongwei^*

来源：AGING CELL, 2011, 10(5): 807-823.

DOI：10.1111/j.1474-9726.2011.00721.x

• DLP1/Drp1
• mitochondrial dynamics
• mitochondrial fragmentation
• MPP
• neurotoxicity
• Parkinson's disease

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 mu M 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.

• 出版日期2011-10
• 单位武汉大学