TOR Signaling Couples Oxygen Sensing to Lifespan in C. elegans

Abstract

Summary Metazoans adapt to a low oxygen environment (hypoxia) through activation of stress response pathways. Here we report that transient hypoxia exposure extends lifespan in C. elegans through mitochondrial ROS-dependent regulation of the nutrient sensing kinase TOR and its upstream activator RHEB-1. The increase in lifespan during hypoxia requires the intestinal GATA-type transcription factor, ELT-2, downstream of TOR signaling. Using RNA-Sequencing, we describe an ELT-2-dependent hypoxia response that includes an intestinal glutathione S-transferase, GSTO-1, and uncover that GSTO-1 is required for lifespan under hypoxia. These results indicate mitochondrial ROS-dependent TOR signaling integrates metabolic adaptations to confer survival under hypoxia.

UPRmt-mediated cytoprotection and organismal aging

“…And, ubl-5 was required for the lifespan extension suggesting a requirement for the UPR mt . More recent studies support this findings demonstrating that the level of UPR mt activation correlates with lifespan extension [44], and the requirement for both haf-1 and atfs-1 in the lifespan extension caused by mitochondrial ribosome or respiratory chain perturbation [44, 74]. However, these results are somewhat controversial as a separate study found that atfs-1 (RNAi) and a loss-of-function atfs-1 -mutation failed to suppress the increased longevity conferred by a complex III defect [42].…”

“…C. elegans strains with hypomorphic mutations in respiratory chain and ubiquinone biosynthesis genes including the succinate dehydrogenase component mev-1 (complex II), the cytochrome c reductase component isp-1 (complex III) and the clk-1 gene required for ubiquinone biosynthesis have considerable developmental delays and have been shown to activate the UPR mt [6, 27, 42, 43, 74]. Consistent with a protective role for the UPR mt , the development rate of all three of these mutant worms is further impaired in the absence of ATFS-1 [6, 27, 42].…”

“…To our knowledge, UPR mt activation occurs in all of the mutant and RNAi-treated worms with increased longevity associated with mitochondrial dysfunction, suggesting the UPR mt promotes longevity [43, 44, 74]. However, accumulating data suggest the relationship between the UPR mt and increased longevity is a complicated one [87].…”

GATA transcription factor as a likely key regulator of the Caenorhabditis elegans innate immune response against gut pathogens

“…In addition, ELT-2 was identified as a target for the manipulation of the host's immune defence by Burkholderia pseudomallei , emphasising its role in regulating pathogen-inducible responses. Furthermore, ELT-2 also controls non-infection stress responses in the intestine, such as the response to osmotic stress (Rohlfing et al, 2010), TOR-dependent hypoxia responses (Schieber and Chandel, 2014), and the response to high dietary zinc (Roh et al, 2015). ELT-2 also contributes to life span extension in calorically restricted eat-2 mutants (Zhang et al, 2013) and survival of rpn-10 mutants, which exhibit proteasome dysfunction (Keith et al, 2016).…”

O 2 sensing, mitochondria and ROS signaling: The fog is lifting

“…As hypoxia triggers EGL-9 signaling, this suggests that mitochondria-dependent O 2 sensing could contribute to lifespan extending effects that could be independent of HIF. To test this, Schieber and Chandel exposed either larvae or adult C. elegans to transient hypoxia and observed a significant increase in lifespan 147 . Using RNAi feeding to alter gene expression in intestinal cells, they suppressed the Target of Rapamycin (TOR) homolog ET-363 and found that the hypoxia-induced lifespan extension was abolished.…”