Txnrd3, also known as thioredoxin/glutathione reductase, is a selenoprotein belonging to the Txnrd family. It contains thioredoxin reductase and glutaredoxin domains, and this NADPH-dependent thiol oxidoreductase can reduce both thioredoxin and glutathione in vitro. It is involved in redox regulation, which is crucial for maintaining cellular homeostasis, and has significant importance in male reproduction [1,4,5].

Gene knockout mouse models have been instrumental in uncovering Txnrd3's functions. Txnrd3 knockout male mice exhibit fertility impairment, including lower in vitro fertilization rates, abnormal sperm movement, and an altered thiol redox status in sperm cells. Proteomic analyses suggest TXNRD3 reduces a broad range of substrates during sperm maturation, likely as part of sperm quality control [1]. Redox regulation by TXNRD3 during epididymal maturation is also essential for capacitation-associated mitochondrial activity and sperm motility [4]. Additionally, Txnrd3 knockout enhances Ni-induced lung injury via the VEGF-VEGFR-2 axis [2], and in the kidney, it abolishes the protective effect of melatonin against NiCl2-induced oxidative stress and apoptosis [3]. In the liver, Txnrd3 knockout exacerbates liver fibrosis induced by Ni exposure [6], and in the colon, its suppression promotes colitis and carcinogenesis [7].

In conclusion, Txnrd3 is vital for male fertility through redox regulation of spermatogenesis. Its deficiency also impacts various organs' responses to stressors like Ni exposure, highlighting its role in protecting against oxidative stress-related damage in multiple tissues. The use of Txnrd3 knockout mouse models has provided valuable insights into its functions in male reproduction and disease processes such as lung, kidney, liver, and colon-related pathologies.

References:

1. Dou, Qianhui, Turanov, Anton A, Mariotti, Marco, Chung, Jean-Ju, Gladyshev, Vadim N. 2022. Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesis. In The Journal of biological chemistry, 298, 102183. doi:10.1016/j.jbc.2022.102183. https://pubmed.ncbi.nlm.nih.gov/35753352/

2. Liu, Pinnan, Sun, Yue, Qiao, Senqiu, Cai, Jingzeng, Zhang, Ziwei. 2023. Txnrd3 knockout enhancement of lung injury induced by Ni exposure via the VEGF-VEGFR-2 axis and alleviation of this effect by melatonin. In Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 180, 114032. doi:10.1016/j.fct.2023.114032. https://pubmed.ncbi.nlm.nih.gov/37716496/

3. Xu, Lihua, Guan, Haoyue, Zhang, Xintong, Cai, Jingzeng, Zhang, Ziwei. 2023. Role of Txnrd3 in NiCl2-induced kidney cell apoptosis in mice: Potential therapeutic effect of melatonin. In Ecotoxicology and environmental safety, 265, 115521. doi:10.1016/j.ecoenv.2023.115521. https://pubmed.ncbi.nlm.nih.gov/37757623/

4. Wang, Huafeng, Dou, Qianhui, Jeong, Kyung Jo, Gladyshev, Vadim N, Chung, Jean-Ju. 2022. Redox regulation by TXNRD3 during epididymal maturation underlies capacitation-associated mitochondrial activity and sperm motility in mice. In The Journal of biological chemistry, 298, 102077. doi:10.1016/j.jbc.2022.102077. https://pubmed.ncbi.nlm.nih.gov/35643315/

5. Liu, Aiping, Li, Fengna, Xu, Ping, Gong, Chunmei, Zhou, Ji-Chang. 2022. Gpx4, Selenov, and Txnrd3 Are Three Most Testis-Abundant Selenogenes Resistant to Dietary Selenium Concentrations and Actively Expressed During Reproductive Ages in Rats. In Biological trace element research, 201, 250-259. doi:10.1007/s12011-022-03118-5. https://pubmed.ncbi.nlm.nih.gov/35076866/

6. Liu, Qi, Sun, Yue, Zhu, Yue, Cai, Jingzeng, Zhang, Ziwei. 2022. Melatonin relieves liver fibrosis induced by Txnrd3 knockdown and nickel exposure via IRE1/NF-kB/NLRP3 and PERK/TGF-β1 axis activation. In Life sciences, 301, 120622. doi:10.1016/j.lfs.2022.120622. https://pubmed.ncbi.nlm.nih.gov/35537548/

7. Liu, Qi, Du, Pengyue, Zhu, Yue, Cai, Jingzeng, Zhang, Ziwei. 2022. Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis. In Cellular and molecular life sciences : CMLS, 79, 106. doi:10.1007/s00018-022-04155-y. https://pubmed.ncbi.nlm.nih.gov/35094204/