Redox Signaling of NADPH Oxidases Regulates Oxidative Stress Responses, Immunity and Aging

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.

An adaptive pre-DNA-damage-response protects genome integrity

“…In line with this, antioxidants (including NAC that abrogates RIR), which have been proposed to protect against carcinogenesis, in fact foster lung carcinomas and metastasis (Breau et al, 2019;Le Gal et al, 2015;Wiel et al, 2019). More generally, defect in each of the players of the "Low-stress" response described here (NF-κB, PARP1, FOXO1, DUOX1 and DUOX2) share common phenotypes, such as defects in cell homeostasis and metabolism, ageing and cancer predisposition (Ewald, 2018;Tia et al, 2018;Tilstra et al, 2011;Vida et al, 2016;Little et al, 2017;Park & Hong, 2016;Pires et al, 2018). `…”

The lncRNAs Implicated in Redox Regulation in Ybx1 Deficient Zebrafish Larvae

“…Among them, several lncRNAs as well as mRNAs were found to interact with REDOX-related mRNAs, i.e., duox and noxo1a (Fig 6-B). These two genes have been demonstrated to play important roles in response to oxidative stress (29,30). Also, our functional enrichment analysis indicated that both mRNAs were significantly enriched in the REDOX process, e.g., GO:0006979 (response to oxidative stress) and GO:0055114 (oxidation-reduction process).…”

“…Redox balance is thus critical to embryonic development. More importantly, ROS generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is a crucial redox signal to establish homeostasis (29). This knowledge directs us narrow down the huge number of mRNA-lncRNA interactions to a relatively small subnetwork exhibiting strong correlation to two REDOX-related genes, duox (NADPH oxidase) and noxo1a (NADPH oxidase organizer).…”

Diphenyleneiodonium chloride synergizes with diazoxide to enhance protection against amyloid β induced neurotoxicity

“…Under abnormal conditions of excessive activation, large amounts of ROS can be produced, resulting in oxidative stress damage (Carvalho and Moreira, 2018;Ewald, 2018;Montes et al, 2019). It has been reported that NOX, in particular, NOX2, is implicated in AD (González-Reyes et al, 2017;Jiang et al, 2016).…”