Zebrafish Knockout Reveals Its Role in Regulating Antioxidant Defenses and Aging

Oxidation resistance gene 1 () 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 -knockout zebrafish via the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9) system. Compared with wild-type (WT) zebrafish, mutants exhibited higher mortality and more apoptotic cells under oxidative stress, and multiple antioxidant genes (i.e., , , and ) 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 mutation caused more extensive changes in transcriptional networks compared to WT zebrafish, and several stress response and pro-inflammatory pathways in mutant zebrafish were strongly induced. More importantly, we only observed the activation of the p53 signaling and apoptosis pathway in mutant zebrafish, revealing an important role of in regulating apoptosis via the p53 signaling pathway. Additionally, we found that mutation displayed a shortened lifespan and premature ovarian failure in prolonged observation, which may be caused by the loss of impaired antioxidant defenses, thereby increasing pro-apoptotic events. Altogether, our findings demonstrate that is vital for antioxidant defenses and anti-aging in zebrafish.