Ampd3, adenosine monophosphate deaminase 3, is an isoenzyme involved in regulating the energetic metabolism of mammalian cells. It catalyzes the conversion of AMP to IMP, playing a role in energy charge and nucleotide metabolism [3,5,6].

In a mouse model, genetic ablation of Ampd3 in erythrocytes preserves the adenine nucleotide pool, activates the AMPK-BPGM axis, enhances O₂ delivery and antioxidative stress capacity, protecting against renal hypoxia, damage, and CKD progression. This shows that Ampd3 in erythrocytes is part of a purinergic hypoxia-sensing and energy-regulating axis [1]. In doxorubicin-induced cardiomyopathy, Ampd3 knockout mice have improved ejection fractions and reduced myocardial injury. Transcriptome sequencing revealed reduced levels of related proteins, and it was shown that Ampd3 interacts with HSP90α, leading to mitochondrial fission, ROS release, and ferroptosis [2]. In gastrointestinal stromal tumors (GISTs), depletion of Ampd3 in GIST-T1 cells using siRNA suppressed cell migration and invasion and sensitized cells to imatinib, indicating its association with GIST malignancy [4]. In anthrax LeTx-induced macrophage cell death, a mutant clone with Ampd3 mutation was resistant to LeTx, and restoration of Ampd3 expression re-sensitized cells, suggesting Ampd3 is involved in this cell death mechanism [6]. In autosomal dominant polycystic kidney disease (ADPKD) mouse models, inhibition of Ampd3, a SE-driven and CDK7-controlled metabolic target gene, delays cyst growth [7].

In conclusion, Ampd3 is crucial in energy metabolism-related processes. Studies using gene knockout mouse models have revealed its roles in various disease conditions such as CKD, cardiomyopathy, GISTs, macrophage cell death in anthrax, and ADPKD, providing potential therapeutic targets for these diseases.

References:

1. Chen, Changhan, Xie, TingTing, Zhang, Yujin, D'Alessandro, Angelo, Xia, Yang. 2023. Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model. In Journal of the American Society of Nephrology : JASN, 34, 1647-1671. doi:10.1681/ASN.0000000000000195. https://pubmed.ncbi.nlm.nih.gov/37725437/

2. Cheng, Liting, Zhu, Mingxiang, Xu, Xiang, Liu, Chunlei, He, Kunlun. 2024. AMPD3 promotes doxorubicin-induced cardiomyopathy through HSP90α-mediated ferroptosis. In iScience, 27, 111005. doi:10.1016/j.isci.2024.111005. https://pubmed.ncbi.nlm.nih.gov/39474068/

3. Hsu, Cheng-Ming, Chang, Shun-Fu, Tsai, Yao-Te, Lin, Sheng-Fung, Yang, Ming-Yu. . Down-regulation of AMPD3 Is Associated With Poor Survival in Head and Neck Squamous Cell Carcinoma. In In vivo (Athens, Greece), 36, 704-712. doi:10.21873/invivo.12756. https://pubmed.ncbi.nlm.nih.gov/35241525/

4. Wong, Meihong, Funasaka, Kohei, Obayashi, Tomohiko, Goto, Hidemi, Senga, Takeshi. 2016. AMPD3 is associated with the malignant characteristics of gastrointestinal stromal tumors. In Oncology letters, 13, 1281-1287. doi:10.3892/ol.2016.5532. https://pubmed.ncbi.nlm.nih.gov/28454247/

5. Cheng, Jidong, Morisaki, Hiroko, Toyama, Keiko, Okabe, Masaru, Morisaki, Takayuki. 2012. AMPD3-deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency. In Genes to cells : devoted to molecular & cellular mechanisms, 17, 913-22. doi:10.1111/gtc.12006. https://pubmed.ncbi.nlm.nih.gov/23078545/

6. Lee, Sangun, Wang, Yanhai, Kim, Sung Ouk, Han, Jiahuai. 2011. AMPD3 is involved in anthrax LeTx-induced macrophage cell death. In Protein & cell, 2, 564-72. doi:10.1007/s13238-011-1078-2. https://pubmed.ncbi.nlm.nih.gov/21822801/

7. Mi, Zeyun, Song, Yandong, Cao, Xinyi, Zhang, Lirong, Chen, Yupeng. 2020. Super-enhancer-driven metabolic reprogramming promotes cystogenesis in autosomal dominant polycystic kidney disease. In Nature metabolism, 2, 717-731. doi:10.1038/s42255-020-0227-4. https://pubmed.ncbi.nlm.nih.gov/32694829/