Aifm2, also known as Ferroptosis suppressor protein 1 (FSP1) and Apoptosis-inducing factor mitochondria-associated 2, is a crucial NADH oxidase. It is involved in regulating cytosolic NAD+ and plays roles in multiple biological pathways, such as those related to apoptosis, ferroptosis, mitochondrial biogenesis, and glycolysis [2,3,4,5,6]. Genetic models, like gene knockout mouse models, are valuable tools to study its functions.

In severe acute pancreatitis (SAP) mouse models, knockout of ATF6, which is associated with Aifm2 regulation, attenuated acinar injury, apoptosis, and ER disorder. Aifm2 was identified as a downstream regulatory partner of ATF6, and its expression increased in SAP. Functionally, Aifm2 could re-establish the pathological disorder in SAP tissues in the absence of ATF6 [1]. In hepatocellular carcinoma (HCC), knockdown of Aifm2 significantly impaired the metastasis of HCC both in vitro and in vivo, indicating its role in promoting HCC metastasis [2]. In skeletal muscle, muscle-specific Aifm2 depletion decreased exercise capacity and glucose utilization in mice, suggesting its importance in high-intensity aerobic exercise-promoted glucose utilization [3].

In conclusion, Aifm2 is essential in processes like apoptosis, metastasis, and glucose utilization. Gene knockout mouse models have revealed its significance in diseases such as severe acute pancreatitis and hepatocellular carcinoma, providing insights into potential therapeutic targets for these diseases.

References:

1. Tan, Jie-Hui, Cao, Rong-Chang, Zhou, Lei, Jin, Jin, Zhang, Guo-Wei. 2020. ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. In Theranostics, 10, 8298-8314. doi:10.7150/thno.46934. https://pubmed.ncbi.nlm.nih.gov/32724472/

2. Guo, Sanxing, Li, Fengying, Liang, Yixuan, Yang, Qi, Liu, Junqi. 2023. AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling. In Oncogenesis, 12, 46. doi:10.1038/s41389-023-00491-1. https://pubmed.ncbi.nlm.nih.gov/37735151/

3. Nguyen, Hai P, Villivalam, Sneha Damal, Jung, Byung Chul, Sul, Hei Sook, Kang, Sona. . AIFM2 Is Required for High-Intensity Aerobic Exercise in Promoting Glucose Utilization. In Diabetes, 71, 2084-2093. doi:10.2337/db21-1114. https://pubmed.ncbi.nlm.nih.gov/35772021/

4. Bersuker, Kirill, Hendricks, Joseph M, Li, Zhipeng, Dixon, Scott J, Olzmann, James A. 2019. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. In Nature, 575, 688-692. doi:10.1038/s41586-019-1705-2. https://pubmed.ncbi.nlm.nih.gov/31634900/

5. Doll, Sebastian, Freitas, Florencio Porto, Shah, Ron, Angeli, José Pedro Friedmann, Conrad, Marcus. 2019. FSP1 is a glutathione-independent ferroptosis suppressor. In Nature, 575, 693-698. doi:10.1038/s41586-019-1707-0. https://pubmed.ncbi.nlm.nih.gov/31634899/

6. Dai, Enyong, Zhang, Wenlong, Cong, Dan, Wang, Jing, Tang, Daolin. 2020. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. In Biochemical and biophysical research communications, 523, 966-971. doi:10.1016/j.bbrc.2020.01.066. https://pubmed.ncbi.nlm.nih.gov/31964528/