Fis1-KO Mouse

Fis1, short for mitochondrial fission 1 protein, is a key component in mitochondrial fission processes. It is involved in regulating mitochondrial dynamics, which is crucial for maintaining mitochondrial function, including processes like energy production (ATP synthesis), oxidative stress regulation, and apoptosis. The Drp1/Fis1 interaction is a well-studied pathway in mitochondrial fission [3,5,6]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be used to study Fis1's functions in vivo.

In sepsis-induced acute kidney injury (SAKI), lactate overproduction due to PDHA1 hyperacetylation leads to Fis1 lactylation at lysine 20 (Fis1 K20la). This increase in Fis1 K20la promotes excessive mitochondrial fission, resulting in ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis [1]. In hypoxic pulmonary hypertension, short-term hypoxia-induced SENP1-mediated Fis1 deSUMOylation maintains mitochondrial integrity and endothelial function, while prolonged hypoxia-induced loss of this deSUMOylation causes mitochondrial dysfunction and disease progression [2]. In septic cardiomyopathy, the Drp1/Fis1 interaction drives pathologic fission, leading to mitochondrial dysfunction, and inhibiting this interaction with P110 reduces oxidative stress and cardiac dysfunction [3]. In hepatocellular carcinoma, Met phosphorylates Fis1 at Tyr38 (Fis1 pY38), promoting mitochondrial fission and cancer cell metastasis [4]. In acute kidney injury, inhibiting the Drp1-Fis1 interaction with P110 alleviates aberrant mitochondrial fragmentation and kidney injury [6].

In conclusion, Fis1 is essential for regulating mitochondrial fission and maintaining mitochondrial function. Through studies using KO/CKO mouse models or other loss-of-function experiments, we have gained insights into its role in diseases such as SAKI, hypoxic pulmonary hypertension, septic cardiomyopathy, hepatocellular carcinoma, and acute kidney injury. Understanding Fis1's functions provides potential therapeutic targets for these disease areas.

References:

1. An, Sheng, Yao, Yi, Hu, Hongbin, Chen, Zhongqing, Zeng, Zhenhua. 2023. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. In Cell death & disease, 14, 457. doi:10.1038/s41419-023-05952-4. https://pubmed.ncbi.nlm.nih.gov/37479690/

2. Zhou, Xiaofei, Jiang, Yuanqing, Wang, Yuewen, Simons, Michael, Yu, Luyang. 2023. Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension. In Circulation research, 133, 508-531. doi:10.1161/CIRCRESAHA.122.321200. https://pubmed.ncbi.nlm.nih.gov/37589160/

3. Haileselassie, Bereketeab, Mukherjee, Riddhita, Joshi, Amit U, Bernstein, Daniel, Mochly-Rosen, Daria. 2019. Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. In Journal of molecular and cellular cardiology, 130, 160-169. doi:10.1016/j.yjmcc.2019.04.006. https://pubmed.ncbi.nlm.nih.gov/30981733/

4. Yu, Yan, Peng, Xiao-Dan, Qian, Xiao-Jun, Deng, Rong, Zhu, Xiao-Feng. 2021. Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis. In Signal transduction and targeted therapy, 6, 401. doi:10.1038/s41392-021-00790-2. https://pubmed.ncbi.nlm.nih.gov/34848680/

5. Shi, Wenjia, Tan, Cheng, Liu, Can, Chen, Dan. 2022. Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases. In Reviews in the neurosciences, 34, 275-294. doi:10.1515/revneuro-2022-0056. https://pubmed.ncbi.nlm.nih.gov/36059131/

6. Song, Zhixia, Xia, Yao, Shi, Lang, Wang, Hongtao, Zhu, Jiefu. 2024. Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury. In Cellular & molecular biology letters, 29, 31. doi:10.1186/s11658-024-00553-1. https://pubmed.ncbi.nlm.nih.gov/38439028/