Mdh2, or malate dehydrogenase 2, is a key enzyme of the tricarboxylic acid (TCA) cycle. The TCA cycle is crucial for aerobic respiration, generating energy in the form of ATP, and also provides intermediates for biosynthetic pathways. Thus, Mdh2 is of great biological importance in cellular metabolism [1,2,3,4,5,7,9]. Genetic models, such as gene knockout (KO) mouse models, can be valuable for studying its functions.

MDH2 palmitoylation at cysteine 138 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. Silencing MDH2 represses mitochondrial respiration and ovarian cancer cell proliferation in vitro and in vivo [1]. In fibroblasts, the expression level of MDH2 is positively correlated with cellular senescence. Glibenclamide, which inhibits MDH2 activity, relieves fibroblast senescence in an MDH2 -dependent manner and extends the lifespan of aged mice [2]. Dexmedetomidine alleviates myocardial ischemia-reperfusion injury by inhibiting MDH2 lactylation, as MDH2 lactylation induces ferroptosis and impairs mitochondrial function [3]. In clear cell renal cell carcinoma (ccRCC), knocking out MDH2 promotes cell proliferation, and MDH2 enhances ccRCC sensitivity to ferroptosis inducers by regulating FSP1 ubiquitination [4]. In hepatocellular carcinoma, MDH2 deficiency inhibits cell growth and enhances sensitivity to ferroptosis, and MDH2 stabilizes GPX4 to evade ferroptosis [5]. In gastrointestinal stromal tumors, USP5 promotes ripretinib resistance by MDH2 deubiquitination, and ZDHHC18 can palmitoylate MDH2 to increase its protein stability [6]. In septic-ALI mouse models, MDH2 promotes the cell vitality of primary alveolar epithelial type II cells by promoting glucose intake [7]. In ischemic stroke, microglial lnc-U90926 binds to MDH2, protecting CXCL2 mRNA from MDH2-mediated decay and facilitating neutrophil infiltration [8].

In conclusion, Mdh2 plays essential roles in multiple biological processes and disease conditions. Through model-based research, especially KO mouse models, we've learned that Mdh2 is involved in cancer cell growth, senescence, myocardial injury, and other disease-related processes. These findings provide potential therapeutic targets for treating diseases like ovarian cancer, aging-related conditions, myocardial ischemia-reperfusion injury, and various cancers [1,2,3,4,5,6].

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. Sun, Haoyu, Cui, Zhiwei, Li, Chao, Xu, Zekuan, Xu, Hao. 2024. USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2401171. doi:10.1002/advs.202401171. https://pubmed.ncbi.nlm.nih.gov/38973363/

7. 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/

8. 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/

9. 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/