Gpd2, also known as mitochondrial glycerol 3-phosphate dehydrogenase, is a key component of the glycerol phosphate shuttle. It plays a vital role in regulating glucose oxidation. This process is involved in multiple biological pathways, such as fueling the production of acetyl coenzyme A for histone acetylation, which impacts gene expression related to inflammatory responses and cell metabolism. Genetic models, like knockout (KO) mouse models, are valuable for studying Gpd2's functions [1,3,4,5,6,7,8].

In macrophages, Gpd2 regulates glucose oxidation to drive inflammatory responses. Acute LPS exposure activates macrophages, with Gpd2 promoting glucose oxidation for inflammatory mediator production. Prolonged LPS exposure leads to tolerance, where Gpd2 coordinates a shutdown of oxidative metabolism, suppressing inflammation [1]. In cancer research, KO of Gpd2 in cancer cells, such as hepatocarcinoma-derived HuH-7 and neuroblastoma-derived SH-SY5Y cells, reduces cancer stemness and sphere-forming ability. In vivo, Gpd2 KO suppresses tumor progression, not through its bioenergetic function but by affecting ether lipid metabolism related to the Akt pathway [2,3,5]. In the heart, Gpd2 deficiency exacerbates cardiac dysfunction after acute myocardial infarction, as it is involved in LPL/AQP7/GPD2-mediated glycerol metabolism which prevents myocardial ischemia-related damage [4]. In kidney cancer cells, knocking down Gpd2 upregulates cytosolic GPD and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply for lipid synthesis [6].

In conclusion, Gpd2 is essential in regulating macrophage inflammatory responses, cancer cell stemness and tumor progression, and cardiac function during ischemia. Gene knockout models have significantly contributed to understanding Gpd2's role in these disease-related biological processes, providing insights for potential therapeutic strategies in inflammation-related diseases and cancer [1,2,3,4,5,6].

References:

1. Langston, P Kent, Nambu, Aya, Jung, Jonathan, Snyder, Nathaniel W, Horng, Tiffany. 2019. Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. In Nature immunology, 20, 1186-1195. doi:10.1038/s41590-019-0453-7. https://pubmed.ncbi.nlm.nih.gov/31384058/

2. Mikeli, Maimaiti, Fujikawa, Makoto, Tanabe, Tsutomu. 2022. GPD2: The relationship with cancer and neural stemness. In Cells & development, 173, 203824. doi:10.1016/j.cdev.2022.203824. https://pubmed.ncbi.nlm.nih.gov/36592694/

3. Oh, Sehyun, Jo, Sihyang, Bajzikova, Martina, Neuzil, Jiri, Park, Sunghyouk. 2023. Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. In Theranostics, 13, 438-457. doi:10.7150/thno.75973. https://pubmed.ncbi.nlm.nih.gov/36632231/

4. Ishihama, Sohta, Yoshida, Satoya, Yoshida, Tatsuya, Murohara, Toyoaki, Takefuji, Mikito. . LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e22048. doi:10.1096/fj.202100882R. https://pubmed.ncbi.nlm.nih.gov/34807469/

5. Mikeli, Maimaiti, Fujikawa, Makoto, Nagahisa, Kai, Yamada, Natsuhiko, Tanabe, Tsutomu. 2020. Contribution of GPD2/mGPDH to an alternative respiratory chain of the mitochondrial energy metabolism and the stemness in CD133-positive HuH-7 cells. In Genes to cells : devoted to molecular & cellular mechanisms, 25, 139-148. doi:10.1111/gtc.12744. https://pubmed.ncbi.nlm.nih.gov/31887237/

6. Yao, Cong-Hui, Park, Joon Seok, Kurmi, Kiran, Sharpe, Arlene H, Haigis, Marcia C. . Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis. In Molecular cell, 83, 1340-1349.e7. doi:10.1016/j.molcel.2023.03.023. https://pubmed.ncbi.nlm.nih.gov/37084714/

7. Meng, Jiahui, Zhang, Chunyu, Wang, Danni, Zhu, Lu, Wang, Lingdi. 2022. Mitochondrial GCN5L1 regulates cytosolic redox state and hepatic gluconeogenesis via glycerol phosphate shuttle GPD2. In Biochemical and biophysical research communications, 621, 1-7. doi:10.1016/j.bbrc.2022.06.092. https://pubmed.ncbi.nlm.nih.gov/35802941/

8. Clarke, Raymond A, Govindaraju, Hemna, Beretta, Martina, Turner, Nigel, Siddiqui, Khawar Sohail. 2024. Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase. In International journal of molecular sciences, 25, . doi:10.3390/ijms25020990. https://pubmed.ncbi.nlm.nih.gov/38256063/