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

Aging Cell. 2011 Oct;10(5):807-23. doi: 10.1111/j.1474-9726.2011.00721.x. Epub 2011 Jun 14.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity*
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Autophagy
  • Blotting, Western
  • Cell Line
  • Cell Survival
  • Dynamins / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fluorescent Antibody Technique
  • Fluorescent Dyes / metabolism
  • GTP Phosphohydrolases / metabolism*
  • Gene Silencing
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • Humans
  • Image Processing, Computer-Assisted
  • Membrane Potential, Mitochondrial
  • Microtubule-Associated Proteins / metabolism*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Parkinson Disease / pathology*
  • RNA Interference
  • Rats
  • Reactive Oxygen Species
  • Transfection
  • Tyrosine 3-Monooxygenase / metabolism


  • Excitatory Amino Acid Antagonists
  • Fluorescent Dyes
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Tyrosine 3-Monooxygenase
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dnm1l protein, rat
  • Dynamins
  • 1-Methyl-4-phenylpyridinium