Mdh2, short for malate dehydrogenase 2, is a key enzyme in the tricarboxylic acid (TCA) cycle. The TCA cycle is crucial for cellular energy production through oxidative phosphorylation, and thus Mdh2 is of great biological importance in maintaining normal cellular metabolism. Genetic models, such as KO/CKO mouse models, can be valuable for studying Mdh2's functions [1,2,3,4,5,6,7,8,9,10].

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, its expression level is positively correlated with cellular senescence, and glibenclamide can inhibit MDH2 activity to relieve fibroblast senescence, with in vivo validation in aged mice [2]. Dexmedetomidine ameliorates myocardial ischemia-reperfusion injury by inhibiting MDH2 lactylation, as MDH2 lactylation induces ferroptosis, impairing mitochondrial function [3]. In clear cell renal cell carcinoma (ccRCC), knocking out MDH2 promotes ccRCC proliferation, and MDH2 enhances ccRCC sensitivity to ferroptosis by regulating FSP1 ubiquitination [4]. In hepatocellular carcinoma, MDH2 deficiency inhibits cell growth and enhances ferroptosis sensitivity, 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 primary alveolar epithelial type II cells, MDH2 promotes cell vitality by increasing glucose uptake [7]. In ischemic stroke, lnc-U90926 binds to MDH2, protecting CXCL2 mRNA from MDH2-mediated decay and facilitating neutrophil infiltration [8]. TCA cycle enzymes including Mdh2 translocate to the nucleus during somatic cell reprogramming, and the nuclear-localized ones play roles in epigenetic regulation of pluripotency [9]. Mutations in genes like MDH2 can predispose to multiple pheochromocytoma and paraganglioma [10].

In conclusion, Mdh2 is essential for maintaining normal cellular metabolism through its role in the TCA cycle. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in various disease conditions such as cancer, aging-related phenotypes, and ischemia-reperfusion injury. Understanding Mdh2's functions provides potential therapeutic targets for these diseases.

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/

10. Buffet, Alexandre, Burnichon, Nelly, Favier, Judith, Gimenez-Roqueplo, Anne-Paule. 2020. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. In Best practice & research. Clinical endocrinology & metabolism, 34, 101416. doi:10.1016/j.beem.2020.101416. https://pubmed.ncbi.nlm.nih.gov/32295730/