DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease.
DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson's disease.
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DOI：
10.1111/j.1474-9726.2011.00721.x
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发表时间：
2011-10
期刊：
影响因子：
7.8
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Wang X;Su B;Liu W;He X;Gao Y;Castellani RJ;Perry G;Smith MA;Zhu X
Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson disease (PD) can be modeled by the administration of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Since 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 [Ca2+]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 NAC or glutamate receptor antagonist D-AP5 also partially alleviate 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 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.
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影响因子：
12.4
作者：
Estaquier, J.;Arnoult, D.
通讯作者：
Arnoult, D.
影响因子：
7.4
作者：
Gomez-Lazaro, Maria;Bonekamp, Nina A.;Schrader, Michael
通讯作者：
Schrader, Michael
影响因子：
2.9
作者：
Cheng, Yue-Fa;Zhu, Guo-Qi;Li, Qing-Lin
通讯作者：
Li, Qing-Lin
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
3.3
作者：
Camins, A;Sureda, FX;Camarasa, J
通讯作者：
Camarasa, J