Cisd2, also known as CDGSH iron-sulfur domain 2, is an iron-sulfur protein with a [2Fe-2S] cluster. It is crucial for cell proliferation, iron homeostasis, and maintaining cellular homeostasis, including cytosolic Ca2+ homeostasis, ER integrity, and mitochondrial function. It is associated with pathways like autophagy, p62-Keap1-NRF2, and is related to aging-related diseases, cancers, and lifespan regulation. Genetic models, such as knockout and transgenic mice, have been used to study its functions [1,2,3,4].

In Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and leads to premature aging phenotypes, along with mitochondrial breakdown and dysfunction with autophagic cell death features [4]. In cancer-related studies, knockdown of Cisd2 in cells promotes ferroptosis through ferritinophagy-mediated ferritin turnover and inhibition of the p62-Keap1-NRF2 pathway [1].

In conclusion, Cisd2 is essential for multiple biological functions including lifespan regulation, cellular homeostasis, and iron metabolism. Studies using Cisd2 knockout mouse models have revealed its significance in aging-related diseases and cancer, highlighting its potential as a therapeutic target for these conditions.

References:

1. Li, Yanchun, Xu, Bing, Ren, Xueying, Wang, Ying, Du, Jing. 2022. Inhibition of CISD2 promotes ferroptosis through ferritinophagy-mediated ferritin turnover and regulation of p62-Keap1-NRF2 pathway. In Cellular & molecular biology letters, 27, 81. doi:10.1186/s11658-022-00383-z. https://pubmed.ncbi.nlm.nih.gov/36180832/

2. Liao, Hai-Yang, Liao, Bei, Zhang, Hai-Hong. 2021. CISD2 plays a role in age-related diseases and cancer. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 138, 111472. doi:10.1016/j.biopha.2021.111472. https://pubmed.ncbi.nlm.nih.gov/33752060/

3. Shen, Zhao-Qing, Huang, Yi-Long, Teng, Yuan-Chi, Yeh, Chi-Hsiao, Tsai, Ting-Fen. 2021. CISD2 maintains cellular homeostasis. In Biochimica et biophysica acta. Molecular cell research, 1868, 118954. doi:10.1016/j.bbamcr.2021.118954. https://pubmed.ncbi.nlm.nih.gov/33422617/

4. Wang, C-H, Kao, C-H, Chen, Y-F, Wei, Y-H, Tsai, T-F. 2014. Cisd2 mediates lifespan: is there an interconnection among Ca²⁺ homeostasis, autophagy, and lifespan? In Free radical research, 48, 1109-14. doi:10.3109/10715762.2014.936431. https://pubmed.ncbi.nlm.nih.gov/24974737/