Mitochondrial protein folding disruption leads to recruitment of ATFS-1 in C. elegans to effect the mitochondrial unfolded protein response (mtUPR). Organismal ATFS-1 signaling has been linked to pathogen resistance as well as lifespan extension during prolonged electron-transport chain (ETC) disruption. However, after ETC disruption or successful pathogen avoidance, the mtUPR is presumably shut down to resume normal metabolism and protein regulation. Over-activation of this pathway, especially in the absence of stressors, is not especially well characterized from a cellular health perspective and is relevant to the mechanistic understanding of neurodegenerative disorders linked to mitochondrial dysfunction.
Here we describe consequences of over-activated ATFS-1 signaling in C. elegans neurons. To ascertain the role of cell-autonomous ATFS-1 we overexpressed cDNA construct variants in dopaminergic neurons and found that wild-type overexpression produces neuroanatomical changes including soma swelling. However, a constitutively active variant induces these neuroanatomical changes as well as severe age-dependent degeneration. This degeneration is not seen in variants of ATFS-1 with nuclear import or the bZIP domain mutations, suggesting that it is the altered and ectopic gene expression induced by ATFS-1 which leads to neurodegeneration. Counterintuitively, the ATFS-1 degenerative phenotype can be attenuated by addition of a chronic stressor of the ETC such as rotenone, suggesting that cells may differentiate between chronic and acute signaling paradigms and may implicate organismal signaling mechanisms towards cellular survival. Next, we report a role for α-synuclein (αS), a Parkinson’s disease-associated protein, in altering ATFS-1-mediated toxicity. We find that αS neurotoxicity is enhanced in gof ATFS-1 but reduced in a loss-of-function (lof) mutant. In addition, protein misfolding and αS::GFP bodywall aggregation is reduced in lof ATFS-1 animals suggesting differentially regulated protein handling may underlie ATFS-1 cellular toxicity. We confirmed that ATFS-1 could induce αS toxicity in a cell-autonomous fashion by crossing ATFS-1 cDNA variants into animals that express αS in dopaminergic neurons, finding degrees of age-dependent synergistic toxicity. Lastly, variants on αS possess the ability to differentially induce the mtUPR suggesting that αS may interact with the mitochondria, inducing stress, and potentially influencing cell survival through mechanisms associated with the mtUPR. These findings advance understanding of mitochondrial quality control insofar as organismal signaling and cell-autonomous health coordinate to maintain homeostasis.