Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models

Sci Rep. 2017 Nov 27;7(1):16441. doi: 10.1038/s41598-017-16637-2.


While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Dopamine / pharmacology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • Green Fluorescent Proteins / metabolism
  • Longevity* / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mutation / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Oxidative Stress / drug effects
  • Parkinson Disease / pathology*
  • Unfolded Protein Response* / drug effects


  • Caenorhabditis elegans Proteins
  • Green Fluorescent Proteins
  • Dopamine