Atp6v1d-KO Mouse

Atp6v1d, also known as ATPase H+ transporting V1 subunit D, is a subunit of the vacuolar-type H+-translocating ATPase (V-ATPase). V-ATPase is crucial for maintaining proper cellular pH and is involved in processes like autophagy-lysosomal pathway, which is important for cell metabolism and waste disposal [1,3,4,8].

In hepatocellular carcinoma (HCC), ATP6V1D knockdown inhibits HCC stemness and malignant progression both in vitro and in vivo. Mechanistically, it enhances HCC stemness by maintaining autophagic flux, through promoting lysosomal acidification and facilitating autophagosome-lysosome fusion [1]. In ApoE-/-male mice, five core genes including Atp6v1d were identified in the protein-protein interaction network related to autophagosomes, affecting the development of aortic atherosclerosis through the autophagy-lysosome system [3]. In the context of Alzheimer's disease, ATP6V1D was identified as a biomarker and was downregulated, potentially being a protective factor, and was enriched in inflammation-related pathways [2,5,7]. In a Chinese population, certain polymorphisms in the ATP6V1D promoter region were associated with susceptibility to depression [6].

In summary, Atp6v1d plays essential roles in biological processes related to autophagy-lysosomal function. Research using gene knockout or knockdown models in mice and human genetic studies have revealed its significance in diseases such as HCC, atherosclerosis, Alzheimer's disease, and depression, providing potential therapeutic targets for these conditions.

References:

1. Xu, Zhijie, Liu, Ruiyang, Ke, Haoying, Zhao, Zhiju, Xiao, Fei. 2024. ATP6V1D drives hepatocellular carcinoma stemness and progression via both lysosome acidification-dependent and -independent mechanisms. In Autophagy, 21, 513-529. doi:10.1080/15548627.2024.2406186. https://pubmed.ncbi.nlm.nih.gov/39316516/

2. Zhuang, Xianbo, Xia, Yitong, Liu, Yingli, Wang, Zheng, Zhang, Guifeng. 2024. SCG5 and MITF may be novel markers of copper metabolism immunorelevance in Alzheimer's disease. In Scientific reports, 14, 13619. doi:10.1038/s41598-024-64599-z. https://pubmed.ncbi.nlm.nih.gov/38871989/

3. Zhu, Meirong, Jin, Tongyu, Wu, Ding, Zhang, Shanchao, Wang, Aihua. 2023. Transcriptomics Analysis Revealed Key Genes Associated with Macrophage Autophagolysosome in Male ApoE-/- Mice Aortic Atherosclerosis. In Journal of inflammation research, 16, 5125-5144. doi:10.2147/JIR.S426155. https://pubmed.ncbi.nlm.nih.gov/37965353/

4. Wang, Shaogui, Ni, Hong-Min, Chao, Xiaojuan, Pacher, Pal, Ding, Wen-Xing. 2019. Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. In Autophagy, 15, 1954-1969. doi:10.1080/15548627.2019.1596486. https://pubmed.ncbi.nlm.nih.gov/30894069/

5. Zeng, Junfeng, Zhang, Ruihua, Xu, Huihua, Zhang, Chengwu, Lu, Li. 2025. Integrative single-cell RNA sequencing and mendelian randomization analysis reveal the potential role of synaptic vesicle cycling-related genes in Alzheimer's disease. In The journal of prevention of Alzheimer's disease, 12, 100097. doi:10.1016/j.tjpad.2025.100097. https://pubmed.ncbi.nlm.nih.gov/40021385/

6. Liang, Peng, Chen, Jing-Jie, Yang, Xue, Yang, Ping-Liang, Liang, Yun-Dan. 2025. Association and functional study of ATP6V1D and GPHN gene polymorphisms with depression in Chinese population. In World journal of psychiatry, 15, 102182. doi:10.5498/wjp.v15.i4.102182. https://pubmed.ncbi.nlm.nih.gov/40309610/

7. Duan, KeFei, Ma, Yuan, Tan, Jin, Miao, Yuyang, Zhang, Qiang. 2022. Identification of genetic molecular markers and immune infiltration characteristics of Alzheimer's disease through weighted gene co-expression network analysis. In Frontiers in neurology, 13, 947781. doi:10.3389/fneur.2022.947781. https://pubmed.ncbi.nlm.nih.gov/36071897/

8. Nakadera, Eisuke, Yamashina, Shunhei, Izumi, Kousuke, Ueno, Takashi, Watanabe, Sumio. 2015. Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis. In Biochemical and biophysical research communications, 469, 1104-10. doi:10.1016/j.bbrc.2015.12.010. https://pubmed.ncbi.nlm.nih.gov/26687947/