Abstract
An accumulating body of evidence suggests that transient or physiological reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases act as a redox signal to re-establish homeostasis. The capacity to re-establish homeostasis progressively declines during aging but is maintained in long-lived animals to promote healthy aging. In the model organism Caenorhabditis elegans, ROS generated by dual oxidases (Duox) are important for extracellular matrix integrity, pathogen defense, oxidative stress resistance, and longevity. The Duox enzymatic activity is tightly regulated and under cellular control. Developmental molting cycles, pathogen infections, toxins, mitochondrial-derived ROS, drugs, and small GTPases (e.g., RHO-1) can activate Duox (BLI-3) to generate ROS, whereas NADPH oxidase inhibitors and negative regulators, such as MEMO-1, can inhibit Duox from generating ROS. Three mechanisms-of-action have been discovered for the Duox/BLI-3-generated ROS: (1) enzymatic activity to catalyze crosslinking of free tyrosine ethyl ester in collagen bundles to stabilize extracellular matrices, (2) high ROS bursts/levels to kill pathogens, and (3) redox signaling activating downstream kinase cascades to transcription factors orchestrating oxidative stress and immunity responses to re-establish homeostasis. Although Duox function at the cell surface is well established, recent genetic and biochemical data also suggests a novel role for Duoxs at the endoplasmic reticulum membrane to control redox signaling. Evidence underlying these mechanisms initiated by ROS from NADPH oxidases, and their relevance for human aging, are discussed in this review. Appropriately controlling NADPH oxidase activity for local and physiological redox signaling to maintain cellular homeostasis might be a therapeutic strategy to promote healthy aging.
Highlights
How reactive oxygen species (ROS) influence the rate of aging is an unsolved mystery in biology
Low or acute ROS levels at the physiological level can act as a second messenger to alter cellular signaling, known as redox signaling, and they are important for adaptation against oxidative stress [16,17]
Upon E. faecalis or P. aeruginosa infection, the BLI-3-generated ROS activates p38 MAPK signaling to the transcription factor SKN-1(Nrf1,2,3), thereby eliciting the C. elegans endogenous oxidative stress response in the intestine (Figure 1, [55])
Summary
How reactive oxygen species (ROS) influence the rate of aging is an unsolved mystery in biology. I discuss how the C. elegans Duoxs become activated, and how the generated ROS acts in redox signaling to adapt to oxidative stress and re-establish cellular homeostasis. Blocked BLI-3/Duox-induced ROS production in vivo [13] Together, this suggests that the C. elegans peroxidase and NADPH-oxidase are fully functional, and that calcium might not be required for C. elegans. BLI-3-fused mCherry expression product localizes to the cell membrane of the hypodermis and the apical membrane of the intestine in a punctate-manner [38], reminiscent of the previously mentioned “string-of-pearls” pattern. The C. elegans dual oxidase maturation factor DOXA-1 physically binds to BLI-3/Duox to recruit BLI-3 to the cell membrane [36]. During development BLI-3 generated ROS together with MLT-7 to crosslink collagens
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