Mdh2, short for malate dehydrogenase 2, is a key enzyme in the tricarboxylic acid (TCA) cycle [1,2,3,4,5,6,8]. The TCA cycle is crucial for aerobic respiration, generating energy in the form of ATP and providing intermediates for various biosynthetic pathways. Mdh2 thus plays an important role in central carbon metabolism, which is essential for cell survival, growth, and proliferation [1,2,3,4,5,6,8]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying Mdh2's function [1,2,3,4,5].

MDH2 has been linked to several diseases. In epithelial ovarian cancer, palmitoylation of MDH2 at cysteine 138 by ZDHHC18 activates mitochondrial respiration and accelerates cancer growth. MDH2 silencing represses mitochondrial respiration and ovarian cancer cell proliferation both in vitro and in vivo [1]. In clear cell renal cell carcinoma, knocking out MDH2 enhances the proliferation of cancer cells, and MDH2 promotes ferroptosis and the sensitivity of cancer cells to ferroptosis inducers by regulating the ubiquitination of FSP1 [4]. In hepatocellular carcinoma, MDH2 deficiency inhibits cell growth and enhances sensitivity to ferroptosis, while MDH2 stabilizes GPX4 to evade ferroptosis [5]. Additionally, in ischemic stroke, microglial lnc-U90926 binds to MDH2, protecting CXCL2 mRNA from MDH2-mediated decay and facilitating neutrophil infiltration [7].

In conclusion, Mdh2 is essential for central carbon metabolism through its role in the TCA cycle. Model-based research, especially KO/CKO mouse models, has revealed its significant contributions to cancer development, including ovarian, renal, and hepatocellular carcinomas, as well as its role in ischemic stroke. Understanding Mdh2's functions provides potential therapeutic targets for these diseases [1,4,5,7].

References:

1. Pei, Xuan, Li, Kai-Yue, Shen, Yuan, Qu, Jia, Lei, Qun-Ying. 2022. Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. In Science China. Life sciences, 65, 2017-2030. doi:10.1007/s11427-021-2048-2. https://pubmed.ncbi.nlm.nih.gov/35366151/

2. Mao, Zhifan, Liu, Wenwen, Zou, Rong, Hu, Zelan, Li, Jian. 2025. Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification. In Signal transduction and targeted therapy, 10, 67. doi:10.1038/s41392-025-02157-3. https://pubmed.ncbi.nlm.nih.gov/39962087/

3. She, Han, Hu, Yi, Zhao, Guozhi, Liu, Liangming, Li, Tao. 2024. Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2409499. doi:10.1002/advs.202409499. https://pubmed.ncbi.nlm.nih.gov/39467114/

4. Feng, Baijie, Su, Wei, Guo, Xianzhi, Hu, Lina, Yu, Minghua. 2024. MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1. In Cell death discovery, 10, 363. doi:10.1038/s41420-024-02137-6. https://pubmed.ncbi.nlm.nih.gov/39138167/

5. Yu, Wenjia, Li, Yingping, Gao, Chengchang, Deng, Qinqin, Bian, Xueli. 2024. MDH2 Promotes Hepatocellular Carcinoma Growth Through Ferroptosis Evasion via Stabilizing GPX4. In International journal of molecular sciences, 25, . doi:10.3390/ijms252111604. https://pubmed.ncbi.nlm.nih.gov/39519171/

6. Hu, Mu, Yang, JieLai, Xu, Yang, Liu, Jiao. 2022. MDH1 and MDH2 Promote Cell Viability of Primary AT2 Cells by Increasing Glucose Uptake. In Computational and mathematical methods in medicine, 2022, 2023500. doi:10.1155/2022/2023500. https://pubmed.ncbi.nlm.nih.gov/36158123/

7. Chen, Jian, Jin, Jiali, Zhang, Xi, Xia, Shengnan, Xu, Yun. 2021. Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 2873-2885. doi:10.1016/j.ymthe.2021.04.025. https://pubmed.ncbi.nlm.nih.gov/33895326/

8. Li, Wei, Long, Qi, Wu, Hao, Chan, Wai-Yee, Liu, Xingguo. 2022. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation. In Nature communications, 13, 7414. doi:10.1038/s41467-022-35199-0. https://pubmed.ncbi.nlm.nih.gov/36460681/