Abstract
The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to mitochondria insults through transcriptional changes, mediated by the transcription factor ATFS-1/ATF-5, which acts to restore mitochondrial homeostasis. In this work, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause up-regulation of genes involved in multiple stress response pathways including the DAF-16-mediated stress response pathway, the cytosolic unfolded protein response, the endoplasmic reticulum unfolded protein response, the SKN-1-mediated oxidative stress response pathway, the HIF-1-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, whereas disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are up-regulated in multiple long-lived mutants, constitutive activation of ATFS-1 decreases lifespan in wild-type animals. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stressors through its ability to activate multiple stress response pathways but that chronic ATFS-1 activation is detrimental for longevity.
Highlights
The mitochondrial unfolded protein response is a stress response pathway that acts to reestablish mitochondrial homeostasis by inducing transcriptional changes in genes involved in the metabolism and restoration of mitochondrial protein folding (Zhao et al, 2002)
We find that activation of ATFS-1 is sufficient to up-regulate genes from multiple stress response pathways and is important for transcriptional changes induced by oxidative stress and bacterial pathogen exposure
In exploring the mechanism by which ATFS-1 and the mitochondrial unfolded protein response (mitoUPR) modulate stress resistance, we found that activation of ATFS-1, through mild impairment of mitochondrial function or through constitutive activation of ATFS-1 (atfs-1(et15)), causes upregulation of genes involved in multiple stress response pathways, including the ER unfolded protein response (ER-UPR) pathway, the Cyto-UPR pathway, the DAF16–mediated stress response pathway, the SKN-1–mediated oxidative stress response pathway, the HIF-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes (Fig 2)
Summary
The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that acts to reestablish mitochondrial homeostasis by inducing transcriptional changes in genes involved in the metabolism and restoration of mitochondrial protein folding (Zhao et al, 2002). Various perturbations to the mitochondria can activate mitoUPR, including disruption of mitochondrial translation, disruption of mitochondrial protein synthesis, impairment of oxidative phosphorylation, disruption of mitochondrial proteostasis, altered metabolism, defects in mitochondrial DNA, excess reactive oxygen species (ROS), disruption of protein degradation, and defects in mitochondrial import (Shpilka & Haynes, 2018). The MTS causes ATFS-1 to enter the mitochondria through the HAF-1 import channel. ATFS-1 is degraded by the protease CLPP-1/CLP1 (Nargund et al, 2012). When mitochondrial import or degradation of ATFS-1 is disrupted under conditions of mitochondrial stress, ATFS-1 accumulates in the cytoplasm. The NLS of the cytoplasmic ATFS-1 targets it to the nucleus, where ATFS-1 acts with the transcription factor DVE-1 and transcriptional regulator UBL-5 to up-regulate expression of chaperones, proteases, and other proteins (Jovaisaite et al, 2014)
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