NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

Abstract

Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the C. elegans orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of memo-1 results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of memo-1 or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity.DOI: http://dx.doi.org/10.7554/eLife.19493.001

Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

“…We thus concluded that SKN-1 is a critical transcriptional factor for PQQ-mediated lifespan extension. Our conclusion can be supported by two previous studies showing that SKN-1 mediates BLI-3-dependent ROS in innate immunity (van der Hoeven et al, 2011) and that the impairment of a negative regulator of BLI-3 confers longevity by activating SKN-1 (Ewald et al, 2017).…”

“…Some studies showed that SKN-1 transduces BLI-3-dependent the ROS signal during innate immunity and that the impairment of a negative regulator of BLI-3 activates SKN-1, thereby conferring longevity (Ewald et al, 2017;van der Hoeven et al, 2011), and another study showed that PQQ-mediated lifespan extension requires both SKN-1 and DAF-16 (Wu et al, 2016). We thus addressed whether SKN-1 is involved in PQQ-mediated lifespan extension in our assay system.…”

“…Because of its crucial role in gut immunity, DUOXs are likely to be involved in lifespan regulation (van der Hoeven et al, 2015). Very recently, ROS produced by the C. elegans DUOX BLI-3 was found to extend lifespan in C. elegans (Ewald et al, 2017).…”

Overcoming Autofluorescence to Assess GFP Expression During Normal Physiology and Aging in Caenorhabditis elegans

“…The SKN-1::GFP scoring scheme as described in Robida-Stubbs et al (2012) and Ewald et al (2017b) is divided into four categories: None: no GFP observed in intestinal nuclei;Low: up to one-third of intestinal nuclei show GFP;Medium: more than half of the intestinal nuclei show GFP;High: all intestinal nuclei show GFP (Figure 4A). …”

“…However, RNAi knockdowns or mutations that help to diminish autofluorescence alter gene function and might cause artifacts. In addition, there are transgenic GFP fusions of several stress response-regulating transcription factors (DAF-16::GFP, HSF-1::GFP, HLH-30::GFP, SKN-1::GFP) that are routinely used to assess cytoplasmic to nuclear translocation in intestinal cells as a proxy for their activation (Henderson and Johnson, 2001; Libina et al , 2003; Kwon et al , 2010; Lapierre et al , 2013; Morton and Lamitina, 2013; Ewald et al , 2015 and 2017b). Particularly, the transgenic SKN-1::GFP fusion is barely visible and is masked by intestinal autofluorescence even in larval C. elegans (Havermann et al , 2014; Wang et al , 2016; Hu et al , 2017).…”