Fam3a, a mitochondrial protein, is involved in multiple biological functions. It plays a role in regulating metabolic homeostasis, with its associated pathways including PI3K/AKT, P2 receptor-related signaling, and those related to ATP synthesis and release. It is crucial for processes like cell survival, differentiation, and angiogenesis, and is of great biological importance in various physiological and pathophysiological conditions. Genetic models, such as knockout (KO) mouse models, are valuable for studying its functions [1-10].

In abdominal aortic aneurysm (AAA), FAM3A is decreased in aortas and plasma. Overexpression or supplementation of FAM3A attenuates AAA formation by maintaining VSMC differentiation and inhibiting its transformation. Mechanistically, FAM3A induces KLF4 ubiquitination, reducing its phosphorylation and nuclear localization [1]. In acute kidney injury (AKI), FAM3A is decreased and negatively correlated with tubular cell injury and pyroptosis. KO of FAM3A worsens kidney function decline and promotes tubular cell pyroptosis, while overexpression alleviates these effects by promoting PI3K/AKT/NRF2 signaling and blocking mt-ROS-mediated NLRP3 inflammasome activation [2]. In hepatic steatosis, FAM3A-induced ATP release activates a pathway involving P2 receptor, calmodulin, FOXA2, and CPT2, increasing free fatty acid oxidation and reducing lipid deposition. Imipramine activates this pathway to ameliorate hepatic steatosis [3].

In conclusion, Fam3a is essential for maintaining metabolic and cellular homeostasis. Studies using KO/CKO mouse models have revealed its significant roles in diseases like AAA, AKI, and hepatic steatosis. Understanding Fam3a's functions provides potential therapeutic targets for these and other related diseases.

References:

1. Lei, Chuxiang, Kan, Haoxuan, Xian, Xiangyu, Yang, Dan, Zheng, Yuehong. 2023. FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination. In Nature communications, 14, 5360. doi:10.1038/s41467-023-41177-x. https://pubmed.ncbi.nlm.nih.gov/37660071/

2. Li, Xiaolong, Yuan, Feifei, Xiong, Yabing, Hou, Fan Fan, Zhou, Lili. 2024. FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury. In Redox biology, 74, 103225. doi:10.1016/j.redox.2024.103225. https://pubmed.ncbi.nlm.nih.gov/38875957/

3. Liu, Xiangyang, Hou, Song, Xiang, Rui, Chi, Yujing, Yang, Jichun. 2022. Imipramine activates FAM3A-FOXA2-CPT2 pathway to ameliorate hepatic steatosis. In Metabolism: clinical and experimental, 136, 155292. doi:10.1016/j.metabol.2022.155292. https://pubmed.ncbi.nlm.nih.gov/35995281/