Sod2, also known as superoxide dismutase 2, is a mitochondrial protein belonging to the iron/manganese superoxide dismutase family. Its essential function is to convert the superoxide anion, a potentially damaging radical, to the less reactive hydrogen peroxide, thus playing a crucial role in maintaining redox homeostasis. Sod2 is involved in various pathways such as those related to mitochondrial ROS production, and is important for many biological processes including cell proliferation, differentiation, and tissue repair [3,4,5]. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, have been valuable in studying its functions.

In SIRT3-related studies, Cd exposure decreased SIRT3 expression and activity in HepG2 cells, promoting SOD2 acetylation and reducing its activity, leading to mitochondrial-derived superoxide anion-dependent autophagic cell death. Melatonin treatment enhanced SIRT3 activity, decreased SOD2 acetylation, and suppressed autophagy [1]. In osteoblasts, both SOD2 and SIRT3 knockdown suppressed differentiation, and SIRT3-deficient mice exhibited osteopenia with osteoblast dysfunction, while overexpression of SOD2 or SIRT3 improved the differentiation of primary osteoblasts from SIRT3-deficient mice, indicating SIRT3/SOD2 is vital for osteoblast differentiation and bone formation [2]. In sickle cell disease (SCD), the antioxidant defense system including SOD2 is diminished, and a missense variant in SOD2 is associated with increased sickle complications [7]. In chondrocytes, chondrocyte-specific Sod2 deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, which could be attenuated by β-nicotinamide mononucleotide treatment, highlighting SOD2's role in intervertebral disc redox balance [6].

In conclusion, Sod2 is essential for maintaining redox balance, playing significant roles in processes like autophagy, osteoblast differentiation, and intervertebral disc health. The use of Sod2 KO/CKO mouse models has provided insights into its functions in diseases such as cadmium-induced hepatotoxicity, osteopenia, SCD, and intervertebral disc degeneration. These studies help us understand the underlying mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Pi, Huifeng, Xu, Shangcheng, Reiter, Russel J, Yu, Zhengping, Zhou, Zhou. . SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. In Autophagy, 11, 1037-51. doi:10.1080/15548627.2015.1052208. https://pubmed.ncbi.nlm.nih.gov/26120888/

2. Gao, Jing, Feng, Zhihui, Wang, Xueqiang, Shen, Weili, Liu, Jiankang. 2017. SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. In Cell death and differentiation, 25, 229-240. doi:10.1038/cdd.2017.144. https://pubmed.ncbi.nlm.nih.gov/28914882/

3. Alateyah, Nouralhuda, Gupta, Ishita, Rusyniak, Radoslaw Stefan, Ouhtit, Allal. 2022. SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression. In Molecules (Basel, Switzerland), 27, . doi:10.3390/molecules27030811. https://pubmed.ncbi.nlm.nih.gov/35164076/

4. Flynn, James M, Melov, Simon. 2013. SOD2 in mitochondrial dysfunction and neurodegeneration. In Free radical biology & medicine, 62, 4-12. doi:10.1016/j.freeradbiomed.2013.05.027. https://pubmed.ncbi.nlm.nih.gov/23727323/

5. Li, Yanan, Wang, Tingting, Li, Xiaolei, Shi, Yufang, Shao, Changshun. 2024. SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 1144-1157. doi:10.1016/j.ymthe.2024.01.031. https://pubmed.ncbi.nlm.nih.gov/38310354/

6. Tamagawa, Shota, Sakai, Daisuke, Nojiri, Hidetoshi, Ishijima, Muneaki, Watanabe, Masahiko. 2024. SOD2 orchestrates redox homeostasis in intervertebral discs: A novel insight into oxidative stress-mediated degeneration and therapeutic potential. In Redox biology, 71, 103091. doi:10.1016/j.redox.2024.103091. https://pubmed.ncbi.nlm.nih.gov/38412803/

7. Dosunmu-Ogunbi, Atinuke M, Wood, Katherine C, Novelli, Enrico M, Straub, Adam C. . Decoding the role of SOD2 in sickle cell disease. In Blood advances, 3, 2679-2687. doi:10.1182/bloodadvances.2019000527. https://pubmed.ncbi.nlm.nih.gov/31506286/