Sod3, also known as extracellular superoxide dismutase (EC-SOD), is an antioxidant enzyme. It efficiently catalyzes the dismutation of superoxide anions into hydrogen peroxide in the extracellular spaces [3]. This function is crucial for maintaining cellular redox balance, protecting against oxidative damage, and enhancing cellular resilience [4]. It is involved in multiple signaling pathways such as PI3K/AKT and MAPK [1].

Gene-knockout mouse models have been instrumental in revealing Sod3's roles. Sod3-deficient mice showed a significant decrease in bone mineral density, fat accumulation in the bone marrow cavity, and weakened osteogenesis, indicating its importance in promoting osteogenesis and inhibiting adipogenesis in bone metabolism [1]. In parasite infection, Sod3-deficient mice had a longer survival time and lower parasitemia compared to control mice, suggesting that Sod3 suppresses early cellular immune responses to parasite infection [2]. Placenta-specific Sod3 knockout dams exhibited impaired maternal behavior and decreased prolactin levels, showing that placenta-derived Sod3 promotes maternal behavior via epigenetic programming of the FGF/FGFR-prolactin axis [5]. Global sod3 KO mice were more obese and insulin resistant with enlarged adipose tissue and increased triglyceride accumulation, demonstrating that Sod3 secreted from adipocytes regulates adipose tissue lipid metabolism [6].

In conclusion, Sod3 plays essential roles in bone metabolism, immune response to parasite infection, maternal behavior, and adipose tissue lipid metabolism. The use of Sod3 KO mouse models has significantly contributed to understanding its functions in these biological processes and associated disease-related conditions such as osteoporosis, parasite-related diseases, and obesity-associated metabolic disorders.

References:

1. Xu, Ke, Fei, Wenchao, Gao, Wenxue, Hong, Yang, Cui, Ran. 2023. SOD3 regulates FLT1 to affect bone metabolism by promoting osteogenesis and inhibiting adipogenesis through PI3K/AKT and MAPK pathways. In Free radical biology & medicine, 212, 65-79. doi:10.1016/j.freeradbiomed.2023.12.021. https://pubmed.ncbi.nlm.nih.gov/38141889/

2. Li, Qilong, Lv, Kunying, Jiang, Ning, Cao, Yaming, Chen, Qijun. 2024. SOD3 suppresses early cellular immune responses to parasite infection. In Nature communications, 15, 4913. doi:10.1038/s41467-024-49348-0. https://pubmed.ncbi.nlm.nih.gov/38851821/

3. Zelko, Igor N, Mariani, Thomas J, Folz, Rodney J. . Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. In Free radical biology & medicine, 33, 337-49. doi:. https://pubmed.ncbi.nlm.nih.gov/12126755/

4. Kalmari, Amin, Colagar, Abasalt Hosseinzadeh. 2024. Exploration of SOD3 from gene to therapeutic prospects: a brief review. In Molecular biology reports, 51, 980. doi:10.1007/s11033-024-09919-2. https://pubmed.ncbi.nlm.nih.gov/39269510/

5. Xu, Yidan, Alves-Wagner, Ana B, Inada, Hitoshi, Nagatomi, Ryoichi, Kusuyama, Joji. 2024. Placenta-derived SOD3 deletion impairs maternal behavior via alterations in FGF/FGFR-prolactin signaling axis. In Cell reports, 43, 114789. doi:10.1016/j.celrep.2024.114789. https://pubmed.ncbi.nlm.nih.gov/39325622/

6. Gao, Dan, Hu, Sijun, Zheng, Xuewei, Griffiths, Helen R, Liu, Jiankang. . SOD3 Is Secreted by Adipocytes and Mitigates High-Fat Diet-Induced Obesity, Inflammation, and Insulin Resistance. In Antioxidants & redox signaling, 32, 193-212. doi:10.1089/ars.2018.7628. https://pubmed.ncbi.nlm.nih.gov/31680537/