Lars2, leucyl-tRNA synthetase 2, is an enzyme responsible for synthesizing mitochondrial leucyl-tRNA, crucial for maintaining mitochondrial function. It is involved in pathways like the phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) pathway. Genetic models, especially knockout models, are valuable for studying its functions in various biological processes and disease conditions [1,4,5].

In a KO mouse model, knockout of lars2 in hippocampal neurons led to cognitive impairment as shown by the Barnes maze test, novel object recognition test, and nest-building experiments. Immunofluorescence assays indicated an increase in p-tau, atrophy in the hippocampal region, and a decrease in neurons, suggesting Lars2 is a potential therapeutic target for Alzheimer's disease [1]. In ovarian granulosa cells, silencing of LARS2 inhibited cell proliferation, promoted apoptosis, induced mitochondrial dysfunction and ROS accumulation, which is related to premature ovarian insufficiency (POI) [3]. In colorectal cancer, deletion of Lars2 gene repressed CRC immunoevasion as leucine-tRNA-synthase-2-expressing B cells contribute to CRC immunoevasion [2].

In conclusion, Lars2 is essential for maintaining mitochondrial function. Its knockout models have revealed its roles in diseases such as Alzheimer's disease, POI, and colorectal cancer. These findings contribute to understanding the underlying mechanisms of these diseases and potentially developing new therapeutic strategies.

References:

1. Qian, Wenqi, Yuan, Lin, Zhuge, Weishan, Ni, Haoqi, Lv, Xinhuang. 2024. Regulating Lars2 in mitochondria: A potential Alzheimer's therapy by inhibiting tau phosphorylation. In Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 21, e00353. doi:10.1016/j.neurot.2024.e00353. https://pubmed.ncbi.nlm.nih.gov/38575503/

2. Wang, Zhiqiang, Lu, Zhou, Lin, Shengli, Liu, Ronghua, Chu, Yiwei. 2022. Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion. In Immunity, 55, 1067-1081.e8. doi:10.1016/j.immuni.2022.04.017. https://pubmed.ncbi.nlm.nih.gov/35659337/

3. Feng, Shujun, Wan, Shan, Liu, Shuangying, Bai, Long, Zhu, Yimin. 2022. LARS2 Regulates Apoptosis via ROS-Mediated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Ovarian Granulosa Cells. In Oxidative medicine and cellular longevity, 2022, 5501346. doi:10.1155/2022/5501346. https://pubmed.ncbi.nlm.nih.gov/35585880/

4. Li, Dingfeng, Gao, Xinyi, Ma, Xiaolin, Zhang, Juan, Liu, Qiang. 2024. Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization. In Cell metabolism, 36, 1059-1075.e9. doi:10.1016/j.cmet.2024.02.011. https://pubmed.ncbi.nlm.nih.gov/38458203/

5. Bai, Jingchao, Yan, Meinan, Xu, Yihan, Niu, Liling, Li, Hui. 2024. YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-010463. https://pubmed.ncbi.nlm.nih.gov/39551603/