TY - JOUR
T1 - DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons
T2 - Implications for Parkinson's disease
AU - Wang, Xinglong
AU - Su, Bo
AU - Liu, Wanhong
AU - He, Xiaohua
AU - Gao, Yuan
AU - Castellani, Rudy J.
AU - Perry, George
AU - Smith, Mark A.
AU - Zhu, Xiongwei
PY - 2011/10
Y1 - 2011/10
N2 - 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 0.5μm 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.
AB - 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 0.5μm 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.
KW - DLP1/Drp1
KW - MPP+
KW - Mitochondrial dynamics
KW - Mitochondrial fragmentation
KW - Neurotoxicity
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=80052794422&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052794422&partnerID=8YFLogxK
U2 - 10.1111/j.1474-9726.2011.00721.x
DO - 10.1111/j.1474-9726.2011.00721.x
M3 - Article
C2 - 21615675
AN - SCOPUS:80052794422
SN - 1474-9718
VL - 10
SP - 807
EP - 823
JO - Aging Cell
JF - Aging Cell
IS - 5
ER -