PRKAA2, encoding the AMP-activated protein kinase (AMPK) subunit α2, is crucial in multiple biological processes. AMPK is a key energy-sensing enzyme complex, regulating energy homeostasis by responding to changes in the cellular AMP:ATP ratio. It plays a role in various pathways such as autophagy, metabolism, and cell survival, which are essential for maintaining normal cellular functions [1-5].

In terms of disease-related findings, in the Asian population, variation in PRKAA2, especially at rs2746342, is associated with an increased risk of type 2 diabetes mellitus (T2DM). The G allele is a significant contributing factor to T2DM susceptibility [1]. In hypertensive disorder complicating pregnancy (HDCP), PRKAA2 expression is enhanced in placental tissues. Overexpression accelerates primary placental cell apoptosis, while knockdown attenuates it. SIRT5-mediated PRKAA2 succinylation modulates placental cell apoptosis in HDCP, suggesting it as a potential therapeutic target [2]. In hepatoblastoma (HB) and non-small cell lung cancer (NSCLC), PRKAA2 promotes tumor growth and inhibits ferroptosis. In HB, it regulates HIF-1α and TFR1, and in NSCLC, it activates the SLC7A11/GSH/GPX4 antioxidant pathway [3,4]. In yak renal tubular epithelial cells under chronic hypoxia, PRKAA2-mediated mitophagy is a crucial mechanism for reducing oxygen consumption [5]. In lung adenocarcinoma, miR-186-5p can promote ferroptosis by targeting PRKAA2, inhibiting cancer cell proliferation, invasion, and migration [6].

In conclusion, PRKAA2 is an essential gene involved in energy regulation, autophagy, and metabolism. Its dysregulation is associated with multiple diseases, including T2DM, HDCP, and various cancers. Research on PRKAA2, especially through functional studies in different models, helps us understand the underlying molecular mechanisms of these diseases, providing potential targets for diagnosis, prognosis, and treatment.

References:

1. Virginia, Dita Maria, Dwiprahasto, Iwan, Wahyuningsih, Mae Sri Hartati, Nugrahaningsih, Dwi Aris Agung. 2022. The Effect of PRKAA2 Variation on Type 2 Diabetes Mellitus in the Asian Population: A Systematic Review and Meta-Analysis. In The Malaysian journal of medical sciences : MJMS, 29, 5-16. doi:10.21315/mjms2022.29.3.2. https://pubmed.ncbi.nlm.nih.gov/35846493/

2. Ren, Feifei, Yang, Mo, Liu, Guangman, Li, Jia, Zheng, Lili. 2024. SIRT5-mediated PRKAA2 succinylation ameliorates apoptosis of human placental trophoblasts in hypertensive disorder complicating pregnancy. In Clinical and experimental hypertension (New York, N.Y. : 1993), 46, 2358030. doi:10.1080/10641963.2024.2358030. https://pubmed.ncbi.nlm.nih.gov/38785262/

3. Xie, Yi, Cui, Zhongqi, Fang, Sijia, Pan, Qiuhui, Ma, Ji. 2023. Anti-ferroptotic PRKAA2 serves as a potential diagnostic and prognostic marker for hepatoblastoma. In Journal of gastrointestinal oncology, 14, 1788-1805. doi:10.21037/jgo-23-110. https://pubmed.ncbi.nlm.nih.gov/37720445/

4. Wei, Zhiqiang, Zhou, Zhilian, Zhang, Yu, Xi, Erping, Zeng, Shaoshan. 2024. PRKAA2 Promotes Tumor Growth and Inhibits Ferroptosis through SLC7A11/GSH/GPX4 Pathway in Non-Small Cell Lung Cancer. In Biotechnology and applied biochemistry, , . doi:10.1002/bab.2710. https://pubmed.ncbi.nlm.nih.gov/39722125/

5. Bai, Xuefeng, Lu, Hongqin, Cui, Yan, Yang, Shanshan, He, Junfeng. 2024. PRKAA2-mediated mitophagy regulates oxygen consumption in yak renal tubular epithelial cells under chronic hypoxia. In Cellular signalling, 124, 111450. doi:10.1016/j.cellsig.2024.111450. https://pubmed.ncbi.nlm.nih.gov/39396565/

6. Liu, Lu, Guan, Xin, Zhao, Yanqiao, Liu, Qinghua, Li, Hongli. . [Mechanism of miR-186-5p Regulating PRKAA2 to Promote Ferroptosis 

in Lung Adenocarcinoma Cells]. In Zhongguo fei ai za zhi = Chinese journal of lung cancer, 26, 813-821. doi:10.3779/j.issn.1009-3419.2023.102.39. https://pubmed.ncbi.nlm.nih.gov/38061883/