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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.

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