Open AccessDLP1‐dependent mitochondrial fragmentation mediates 1‐methyl‐4‐phenylpyridinium toxicity in neurons: implications for Parkinson’s disease
Author(s) -
Wang Xinglong,
Su Bo,
Liu Wanhong,
He Xiaohua,
Gao Yuan,
Castellani Rudy J.,
Perry George,
Smith Mark A.,
Zhu Xiongwei
Publication year - 2011
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2011.00721.x
Subject(s) - biology , mitochondrion , neurotoxin , microbiology and biotechnology , tyrosine hydroxylase , programmed cell death , fragmentation (computing) , neurotoxicity , dopaminergic , biochemistry , dopamine , chemistry , neuroscience , toxicity , apoptosis , ecology , organic chemistry
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 [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 μ 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.