Ogdhl-KO Mouse

Ogdh l, also known as oxoglutarate dehydrogenase-like, is one of the rate-limiting components of the key mitochondrial multi-enzyme OGDH complex (OGDHC). It is involved in the tricarboxylic acid cycle, playing a crucial role in the metabolism of glucose and glutamate [1,4]. Through its function in the OGDHC, it impacts the α-ketoglutarate (αKG):citrate ratio and is associated with important cellular processes like lipid metabolism and redox regulation [1].

In hepatocellular carcinoma (HCC), OGDHL knockdown promoted hepatoma cell proliferation in mouse xenograft models, while overexpression inhibited growth. Mechanistically, OGDHL downregulation upregulated the αKG:citrate ratio, driving reductive carboxylation of glutamine-derived αKG and activating the mTORC1 signaling pathway in an αKG-dependent manner, which induced de novo lipogenesis [1]. In clear cell renal cell carcinoma (ccRCC), upregulation of OGDHL expression effectively inhibited ccRCC growth and metastasis both in vitro and in vivo. Low levels of OGDHL promoted TFAP2A expression, which activated FASN expression, promoting lipid accumulation and ERK pathway activation [2]. In kidney renal clear cell carcinoma (KIRC), reduced OGDHL expression was associated with tumor progression and poor prognosis, and was related to differences in the proportion of tumor-infiltrating immune cells [3].

In conclusion, OGDHL is essential in regulating metabolic processes, especially those related to glutamine metabolism and lipid synthesis. Its role in various cancers such as HCC, ccRCC, and KIRC has been revealed through functional studies including gene knockout or overexpression in animal models. These findings suggest that OGDHL could be a potential prognostic biomarker and therapeutic target for these cancers [1,2,3].

References:

1. Dai, Weiqi, Xu, Ling, Yu, Xiangnan, Guo, Chuanyong, Shen, Xizhong. 2019. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. In Journal of hepatology, 72, 909-923. doi:10.1016/j.jhep.2019.12.015. https://pubmed.ncbi.nlm.nih.gov/31899205/

2. Shi, Jian, Miao, Daojia, Lv, Qingyang, Xiong, Zhiyong, Zhang, Xiaoping. 2023. The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling. In Cell death & disease, 14, 560. doi:10.1038/s41419-023-06090-7. https://pubmed.ncbi.nlm.nih.gov/37626050/

3. Xie, Zhouzhou, Chen, Nanhui. 2023. Low OGDHL expression affects the prognosis and immune infiltration of kidney renal clear cell carcinoma. In Translational cancer research, 12, 3045-3060. doi:10.21037/tcr-23-961. https://pubmed.ncbi.nlm.nih.gov/38130311/

4. Jiang, Xiang, Peng, Jin, Xie, Yuanyuan, Han, Junhai, Yu, Decai. 2023. Oxoglutarate dehydrogenase-like inhibits the progression of hepatocellular carcinoma by inducing DNA damage through non-canonical function. In Cell death and differentiation, 30, 1931-1942. doi:10.1038/s41418-023-01186-1. https://pubmed.ncbi.nlm.nih.gov/37419985/