Bckdha, encoding the E1α subunit of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, is crucial for branched-chain amino acid (BCAA) catabolism. The BCKDH complex decarboxylates ketoacid derivatives of leucine, isoleucine, and valine, and this process is part of important metabolic pathways [3,4]. Genetic models, such as knockout mice, are valuable for studying its functions.

In melanoma, Bckdha expression is increased, and its up-regulation promotes tumour cell proliferation, invasion, migration in vitro and tumour growth in vivo by regulating the expressions of lipogenic enzymes FASN and ACLY [1]. In hepatic gluconeogenesis, liver-specific knockout of Bckdha in mice shows normal glucose tolerance and insulin sensitivity, indicating that BCKDH kinase regulates hepatic gluconeogenesis independent of Bckdha-mediated BCAA catabolism [2]. In hepatocellular carcinoma, dephosphorylation of BCKDHA promotes tumorigenesis in vitro and in vivo, and is related to poor prognosis [5]. In cerebral ischemia-reperfusion injury, phosphorylated BCKDHA leads to elevated BCAA levels due to dysfunctional oxidative degradation, and PPM1K affects BCKDHA phosphorylation, which is related to neuronal ferroptosis [6].

In conclusion, Bckdha plays a vital role in BCAA metabolism. Through model-based research, especially KO mouse models, its significance in diseases like melanoma, liver-related metabolic disorders, hepatocellular carcinoma, and cerebral ischemia-reperfusion injury has been revealed. Understanding Bckdha functions provides potential therapeutic targets for these diseases.

References:

1. Tian, Yangzi, Ma, Jingjing, Wang, Mengru, Li, Chunying, Guo, Weinan. 2023. BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY. In Experimental dermatology, 32, 1633-1643. doi:10.1111/exd.14865. https://pubmed.ncbi.nlm.nih.gov/37377173/

2. Zhou, Feiye, Sheng, Chunxiang, Ma, Xiaoqin, Wang, Xiao, Zhou, Libin. 2024. BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA. In Cell death & disease, 15, 736. doi:10.1038/s41419-024-07071-0. https://pubmed.ncbi.nlm.nih.gov/39389936/

3. Blackburn, Patrick R, Gass, Jennifer M, Vairo, Filippo Pinto E, Klee, Eric W, Atwal, Paldeep S. 2017. Maple syrup urine disease: mechanisms and management. In The application of clinical genetics, 10, 57-66. doi:10.2147/TACG.S125962. https://pubmed.ncbi.nlm.nih.gov/28919799/

4. Wang, Jiaming, Poskitt, Laura E, Gallagher, Jillian, Strauss, Kevin A, Wang, Dan. 2025. BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease. In Science translational medicine, 17, eads0539. doi:10.1126/scitranslmed.ads0539. https://pubmed.ncbi.nlm.nih.gov/40009698/

5. Yang, Dongdong, Liu, Haiying, Cai, Yongping, Zhang, Huafeng, Gao, Ping. . Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression. In Cell reports, 41, 111691. doi:10.1016/j.celrep.2022.111691. https://pubmed.ncbi.nlm.nih.gov/36417878/

6. Li, Tao, Zhao, Lili, Li, Ye, Kuang, Fang, Zhang, Guilian. 2023. PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons. In Cell death & disease, 14, 634. doi:10.1038/s41419-023-06135-x. https://pubmed.ncbi.nlm.nih.gov/37752100/