Abstract
Oxidation resistance gene 1 (OXR1) is essential for protection against oxidative stress in mammals, but its functions in non-mammalian vertebrates, especially in fish, remain uncertain. Here, we created a homozygous oxr1a-knockout zebrafish via the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9) system. Compared with wild-type (WT) zebrafish, oxr1a−/− mutants exhibited higher mortality and more apoptotic cells under oxidative stress, and multiple antioxidant genes (i.e., gpx1b, gpx4a, gpx7 and sod3a) involved in detoxifying cellular reactive oxygen species were downregulated significantly. Based on these observations, we conducted a comparative transcriptome analysis of early oxidative stress response. The results show that oxr1a mutation caused more extensive changes in transcriptional networks compared to WT zebrafish, and several stress response and pro-inflammatory pathways in oxr1a−/− mutant zebrafish were strongly induced. More importantly, we only observed the activation of the p53 signaling and apoptosis pathway in oxr1a−/− mutant zebrafish, revealing an important role of oxr1a in regulating apoptosis via the p53 signaling pathway. Additionally, we found that oxr1a mutation displayed a shortened lifespan and premature ovarian failure in prolonged observation, which may be caused by the loss of oxr1a impaired antioxidant defenses, thereby increasing pro-apoptotic events. Altogether, our findings demonstrate that oxr1a is vital for antioxidant defenses and anti-aging in zebrafish.
Highlights
Reactive oxygen species (ROS) are a byproduct of aerobic metabolism
We examined the role of oxr1a in genome-wide transcription regulation by transcriptome sequencing (RNA-seq), revealing the importance of oxr1a for balancing transcriptional networks, regulating the early oxidative stress response and modulating apoptosis
By Gene Ontology (GO) enrichment analysis, we further revealed that several biological processes associated with early stress response were activated in oxr1a−/− mutants, but none of these occurred in WT zebrafish
Summary
Reactive oxygen species (ROS) are a byproduct of aerobic metabolism. It has been established that, in eukaryotic cells, mitochondria are an important source of ROS production [1]. Low amounts of ROS have beneficial effects on many essential biological processes such as angiogenesis [2], wound healing [3], the killing of invading pathogens [4] and tissue repair [5]. The excessive generation of ROS causes serious problems to bodily homeostasis and leads to an accumulation of oxidative DNA damage and spontaneous mutagenesis [6,7,8], which are associated with diseases including neurodegeneration, cancer and aging [9,10,11]. Oxidation resistance 1 (OXR1) is a conserved gene family that only occurs in eukaryotes and is mainly participates in the protection against deleterious ROS.
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