Suclg2, the succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β, is a key enzyme in the tricarboxylic acid (TCA) cycle. It catalyzes the conversion of succinyl-CoA to succinate, generating GTP in the process, which is crucial for energy metabolism in mitochondria. This function is essential for maintaining normal cellular energy homeostasis and is involved in various biological processes related to mitochondrial function [1,2,3,4,5].

In lung adenocarcinoma (LUAD), deletion of SUCLG2 in LUAD cells can upregulate the succinylation level of mitochondrial proteins, inhibit the function of key metabolic enzymes, and dampen mitochondrial function. Moreover, SUCLG2 itself is succinylated on Lys93, enhancing its protein stability and promoting LUAD cell proliferation and tumorigenesis [1].

In regulatory dendritic cells (diffDCs), interference with Suclg2 impairs their tolerogenic function in inducing T-cell apoptosis and enhances NF-κB signaling activation and inflammatory gene expression. This indicates that Suclg2 is required to maintain the immunoregulatory function of diffDCs [2].

In pheochromocytoma and paraganglioma (PPGL), germline variants in the guanosine triphosphate-binding domain of SUCLG2 lead to absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, faulty assembly of complex II, aberrant respiration, and elevated succinate accumulation, suggesting SUCLG2 as a novel candidate gene in the genetic landscape of PPGL [3].

In summary, Suclg2 is vital for maintaining mitochondrial function and energy metabolism. Model-based research, such as gene deletion studies in LUAD cells, interference in diffDCs, and analysis of germline variants in PPGL patients, has revealed its roles in cancer development and immune regulation. These findings contribute to our understanding of the underlying mechanisms of these diseases and may provide potential targets for therapeutic intervention.

References:

1. Hu, Qifan, Xu, Jing, Wang, Lei, Han, Tianyu, Wang, Jian-Bin. 2023. SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2303535. doi:10.1002/advs.202303535. https://pubmed.ncbi.nlm.nih.gov/37904651/

2. Zhang, Xiaomin, Liu, Juan, Cheng, Yujie, Liu, Shuxun, Cao, Xuetao. 2023. Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation. In Journal of autoimmunity, 138, 103048. doi:10.1016/j.jaut.2023.103048. https://pubmed.ncbi.nlm.nih.gov/37216870/

3. Hadrava Vanova, Katerina, Pang, Ying, Krobova, Linda, Yang, Chunzhang, Pacak, Karel. . Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma. In Journal of the National Cancer Institute, 114, 130-138. doi:10.1093/jnci/djab158. https://pubmed.ncbi.nlm.nih.gov/34415331/

4. Lin, Shian-Ren, Wen, Yu-Ching, Yeh, Hsiu-Lien, Chen, Wei-Yu, Liu, Yen-Nien. 2020. EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. In Oncogene, 39, 6757-6775. doi:10.1038/s41388-020-01468-9. https://pubmed.ncbi.nlm.nih.gov/32963351/

5. Wu, Bowen, Qiu, Jingtao, Zhao, Tuantuan V, Goronzy, Jörg J, Weyand, Cornelia M. . Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells. In Cell metabolism, 32, 967-980.e5. doi:10.1016/j.cmet.2020.10.025. https://pubmed.ncbi.nlm.nih.gov/33264602/