Got1-KO Mouse

GOT1, also known as cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in multiple metabolic pathways vital for cellular homeostasis. It is involved in classical and non-classical glutamine metabolism, glycolytic metabolism, and other pathways, and is crucial for maintaining redox balance [2].

In pancreatic cancer, GOT1 inhibition promotes ferroptosis, an oxidative, iron-dependent form of cell death. Pharmacological inhibition shows that cysteine, glutathione, and lipid antioxidant function are metabolic vulnerabilities following GOT1 withdrawal. Mechanistically, GOT1 inhibition represses mitochondrial metabolism, promotes a catabolic state, enhances labile iron availability through autophagy, and potentiates the activity of ferroptotic stimuli [1].

In CD8+ T cells, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells, while GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis, and promotes glycolytic programming and cytotoxic function of cytotoxic T lymphocytes [3].

In conclusion, GOT1 is essential for maintaining cellular metabolic balance, especially in redox-related metabolic regulation. Studies using gene knockout models, such as in pancreatic cancer and CD8+ T cells, have revealed its role in disease-related processes like ferroptosis and T-cell differentiation. These findings contribute to understanding the mechanisms of cancer and immune-related diseases, potentially providing new targets for treatment.

References:

1. Kremer, Daniel M, Nelson, Barbara S, Lin, Lin, Olive, Kenneth P, Lyssiotis, Costas A. 2021. GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. In Nature communications, 12, 4860. doi:10.1038/s41467-021-24859-2. https://pubmed.ncbi.nlm.nih.gov/34381026/

2. Peng, Huan, Dou, Huihong, He, Sheng, Zhang, Qinle, Zheng, Jianqiu. 2024. The role of GOT1 in cancer metabolism. In Frontiers in oncology, 14, 1519046. doi:10.3389/fonc.2024.1519046. https://pubmed.ncbi.nlm.nih.gov/39777342/

3. Xu, Wei, Patel, Chirag H, Zhao, Liang, Wen, Jiayu, Powell, Jonathan D. 2023. GOT1 regulates CD8+ effector and memory T cell generation. In Cell reports, 42, 111987. doi:10.1016/j.celrep.2022.111987. https://pubmed.ncbi.nlm.nih.gov/36640309/