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.
Highlights
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/Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, thereby stimulating reactive oxygen species (ROS) production that signal via p38 MAP kinase to the transcription factor SKN-1/ NRF1,2,3 to promote stress resistance and longevity
We found that loss of the C. elegans memo-1/ C37C3.8 leads to elevated ROS levels generated by BLI-3/NADPH oxidase, which activates an adaptive detoxification system regulated by the transcription factor SKN-1/Nrf1,2,3 in promoting organismal-wide oxidative stress resistance and longevity
To gain insight into the biological function of memo-1 in C. elegans, we took a reverse genetics approach using memo-1 RNA interference (memo-1(RNAi)) or memo-1(gk345) putative null mutants (memo-1(-); Figure 1B) and measured longevity. Both memo-1(RNAi)) and memo-1(gk345) mutants showed a 7–38% increase in lifespan compared to wild type (Figure 1C, Supplementary file 1). We tested these mutants for several pathways related to Memo1 activities in vertebrates (Sorokin and Chen, 2013; Marone et al, 2004), which include phenotypes linked to the epidermal growth factor receptor (EGFR) and insulin/IGF-1 receptors (Figure 1—figure supplement 2E), and to cell migration (Figure 1—figure supplement 2F–J)
Summary
How reactive oxygen species (ROS) affect aging is a fundamental issue in biology (Back et al, 2012a; Krause, 2007; Hekimi et al, 2011; Ristow, 2014; Ristow and Schmeisser, 2014; Kawagishi and Finkel, 2014; Riera and Dillin, 2015; Durieux et al, 2011; Balaban et al, 2005; Melov, 2002; Shadel, 2014; Sena and Chandel, 2012). Low or acute ROS exposure mobilizes protective mechanisms and increases lifespan in S. cerevisiae (Pan et al, 2011; Mesquita et al, 2010; Schroeder et al, 2013), D. melanogaster (Albrecht et al, 2011), C. elegans (Schulz et al, 2007; Doonan et al, 2008; Yang and Hekimi, 2010; Schmeisser et al, 2013; Lee et al, 2010), and rodents (Lapointe and Hekimi, 2008; Liu et al, 2005), and has been associated with health benefits in humans (Ristow et al, 2009, 2014) This phenomenon is conceptualized as mitochondrial hormesis or mitohormesis (Ristow and Schmeisser, 2014).
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