Cisd1, also known as CDGSH iron sulfur domain 1 or mitoNEET, is a protein localized on the outer membrane of mitochondria. It contains an iron-sulfur cluster and plays key roles in regulating cell death, oxidative stress, mitochondrial oxidative capacity, and cellular bioenergetics. It is involved in pathways such as those related to mitochondrial quality control, and is associated with various biological processes including ferroptosis [2,3,4,5,6,7]. Genetic models, like Drosophila and mouse models, have been crucial in studying Cisd1's functions [1,7].

In a Drosophila model, Cisd (the Drosophila ortholog of CISD1) accumulates in Pink1 and parkin mutant flies, blocking mitophagy and leading to neurodegenerative phenotypes. Reducing Cisd levels genetically or pharmacologically ameliorates these phenotypes, suggesting that CISD1 accumulation is a key driver of pathology in neurodegeneration related to Pink1/parkin mutations [1]. In mice, inhibition of CISD1 with NL-1 attenuates cisplatin-induced hearing loss by reducing reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways [4].

In conclusion, Cisd1 is essential for maintaining mitochondrial function and regulating processes like mitophagy, oxidative stress, and cell death. Studies using gene-knockout or knockdown models in Drosophila and mice have revealed its role in neurodegenerative diseases and cisplatin-induced ototoxicity. Understanding Cisd1's functions provides potential therapeutic targets for these disease areas.

References:

1. Martinez, Aitor, Sanchez-Martinez, Alvaro, Pickering, Jake T, Chen, Chun-Hong, Whitworth, Alexander J. 2024. Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models. In Molecular neurodegeneration, 19, 12. doi:10.1186/s13024-024-00701-3. https://pubmed.ncbi.nlm.nih.gov/38273330/

2. Su, Lianjiu, Zhang, Jiahao, Gomez, Hernando, Kellum, John A, Peng, Zhiyong. 2022. Mitochondria ROS and mitophagy in acute kidney injury. In Autophagy, 19, 401-414. doi:10.1080/15548627.2022.2084862. https://pubmed.ncbi.nlm.nih.gov/35678504/

3. Lu, Tailiang, Li, Chenglong, Xiang, Cailing, Peng, Wei, Chen, Chaowu. 2022. Overexpression of CISD1 Predicts Worse Survival in Hepatocarcinoma Patients. In BioMed research international, 2022, 7823191. doi:10.1155/2022/7823191. https://pubmed.ncbi.nlm.nih.gov/35313629/

4. Dong, Wenqi, Jiang, Yumeng, Yao, Qingxiu, Li, Zhuangzhuang, Yu, Dongzhen. 2024. Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways. In Biochemical pharmacology, 223, 116132. doi:10.1016/j.bcp.2024.116132. https://pubmed.ncbi.nlm.nih.gov/38492782/

5. Wang, Haixia, Jia, Yuanmin, Gu, Junlian, Chen, Ou, Yue, Shouwei. 2023. Ferroptosis-related genes are involved in asthma and regulate the immune microenvironment. In Frontiers in pharmacology, 14, 1087557. doi:10.3389/fphar.2023.1087557. https://pubmed.ncbi.nlm.nih.gov/36843917/

6. Hua, Jinghai, Gao, Zhiming, Zhong, Shaochun, Zhu, Jianbing, Ying, Ru. 2021. CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1. In Biochemical and biophysical research communications, 577, 80-88. doi:10.1016/j.bbrc.2021.08.023. https://pubmed.ncbi.nlm.nih.gov/34509082/

7. Bitar, Sara, Baumann, Timo, Weber, Christopher, Zhang, Li, Methner, Axel. 2024. Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes. In eLife, 13, . doi:10.7554/eLife.97027. https://pubmed.ncbi.nlm.nih.gov/39159312/