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

Aging Cell

Xinglong Wang¹  Bo Su¹  Wanhong Liu³  Xiaohua He³  Yuan Gao¹  Rudy J. Castellani²  George Perry¹  Mark A. Smith¹ 

[1] Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;Department of Pathology, University of Maryland, Baltimore, MD 21201, USA;School of Medicine, Wuhan University, Wuhan, Hubei 430072, China

关键词: DLP1/Drp1;    mitochondrial dynamics;    mitochondrial fragmentation;    MPP+;    neurotoxicity;    Parkinson’s disease;   

DOI  :  10.1111/j.1474-9726.2011.00721.x

来源: Wiley

【 摘 要 】

Summary

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 [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 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.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland