Ldhb-KO Mouse

Ldhb, lactate dehydrogenase B, is an enzyme in the glycolysis pathway. It reversibly catalyzes the conversion between pyruvate and lactate, playing a role in cellular metabolism. When oxygen is abundant, it preferentially converts lactate to pyruvate and NAD+ to NADH [2,3,4]. Ldhb is involved in multiple biological processes, influencing energy metabolism and cell death regulation [2].

In CSFV infection, knockdown of Ldhb via interfering RNA induced mitochondrial fission and mitophagy, promoted NFKB signaling regulated by mitophagy, inhibited apoptosis, and ultimately facilitated CSFV growth. Overexpression of Ldhb decreased CSFV replication, revealing its role in mediating CSFV infection [1].

In breast cancer cells, decreased Ldhb expression caused NK cell activation, promoting tumor cell metastasis. Ldhb -mediated lactic acid clearance in breast cancer cells triggered NK cell activation within the tumor microenvironment, affecting immune cell infiltration and function [5].

In ovarian cancer, knockdown of Ldhb inhibited cell growth, glucose uptake, lactate production, and ATP production, enhanced the killing effects of T cells, and increased the production of immune activation factors. Ldhb regulated the H3K18 lactylation modification on PD-L1 promoter region to promote its expression, participating in the immune evasion of ovarian cancer cells [6].

In the brain, LDHB-deficient mice showed increased neuronal survival following ischemic insult due to elevated lactate-induced vasodilation [7]. However, Ldhb deficiency in adult mouse brain promoted mitochondrial dysfunction-mediated oxidative stress and neurodegeneration, as Ldhb -/- mice had enhanced ROS and LPO production, depleted cellular ATP, and downregulated Nrf2 and HO-1 proteins, along with cognitive deficits [8].

In conclusion, Ldhb is crucial for maintaining normal cellular metabolism, especially in energy-related processes. Through gene-knockout mouse models, its roles in various diseases have been revealed. In viral infections like CSFV, it impacts the infection process through regulating mitophagy and apoptosis. In cancers such as breast and ovarian cancer, it influences the tumor microenvironment and immune evasion. In the brain, it affects ischemic resistance and neurodegeneration. These findings from model-based research provide insights into the mechanisms of these diseases and potential therapeutic targets related to Ldhb.

References:

1. Fan, Shuangqi, Wu, Keke, Zhao, Mingqiu, Yi, Lin, Chen, Jinding. 2020. LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection. In Autophagy, 17, 2305-2324. doi:10.1080/15548627.2020.1823123. https://pubmed.ncbi.nlm.nih.gov/32924761/

2. Urbańska, Kaja, Orzechowski, Arkadiusz. 2019. Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells. In International journal of molecular sciences, 20, . doi:10.3390/ijms20092085. https://pubmed.ncbi.nlm.nih.gov/31035592/

3. Hong, Weilong, Zeng, Xue, Wang, Houping, Huang, He, Duan, Chenyang. 2024. PGC-1α loss promotes mitochondrial protein lactylation in acetaminophen-induced liver injury via the LDHB-lactate axis. In Pharmacological research, 205, 107228. doi:10.1016/j.phrs.2024.107228. https://pubmed.ncbi.nlm.nih.gov/38810904/

4. Zhang, Peng, Wan, Yi, Ma, Jinrong, Tan, Youwen, Zhang, Chengsheng. 2024. Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment. In Cancer immunology, immunotherapy : CII, 73, 127. doi:10.1007/s00262-024-03717-2. https://pubmed.ncbi.nlm.nih.gov/38739169/

5. Luo, Zhihong, Huang, Xiaohua, Xu, Xinyi, Gong, Ke, Li, Wenhua. . Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression. In Cancer biology & medicine, 21, 513-40. doi:10.20892/j.issn.2095-3941.2023.0382. https://pubmed.ncbi.nlm.nih.gov/38525901/

6. Hu, Xuemei, Huang, Zhenqiang, Li, Lingyun. 2024. LDHB Mediates Histone Lactylation to Activate PD-L1 and Promote Ovarian Cancer Immune Escape. In Cancer investigation, 43, 70-79. doi:10.1080/07357907.2024.2430283. https://pubmed.ncbi.nlm.nih.gov/39587817/

7. Lee, Jin Soo, Yoon, Bok Seon, Kim, Yihyang, Park, Chan Bae. 2024. LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation. In Biochemical and biophysical research communications, 734, 150766. doi:10.1016/j.bbrc.2024.150766. https://pubmed.ncbi.nlm.nih.gov/39368368/

8. Park, Jun Sung, Saeed, Kamran, Jo, Myeung Hoon, Lee, Gwang, Kim, Myeong Ok. 2022. LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain. In Antioxidants (Basel, Switzerland), 11, . doi:10.3390/antiox11020261. https://pubmed.ncbi.nlm.nih.gov/35204143/