Ucp2, an uncoupling protein homolog to UCP1, is a mitochondrial anion carrier protein. It uncouples oxidative phosphorylation from ATP production by dissipating the proton gradient across the mitochondrial inner membrane, regulating mitochondrial ATP production and reactive oxygen species (ROS) generation [2,3]. Ucp2 is involved in multiple pathways, such as those related to oxidative stress, cellular metabolism, and inflammation, and is of great biological importance in processes like healthy ageing, cerebro-and cardiovascular protection [2]. Genetic models, like KO mouse models, are valuable for studying its functions.

In endothelial cells, EC-specific Ucp2 knockout mice were used to study atherosclerosis. Deletion of Ucp2 in endothelial cells promotes atherogenesis and collagen production, while its overexpression inhibits carotid atherosclerotic plaque formation. Ucp2 knockdown in endothelial cells induces a pro-inflammatory and profibrotic phenotype, and RNA-sequencing analysis reveals FoxO1 as a major proinflammatory transcriptional regulator activated by Ucp2 knockdown. Also, Ucp2 level is critical for phosphorylation of AMPK, which is required for Ucp2-induced inhibition of FoxO1 [1]. In podocytes, podocyte-specific Ucp2-KO mice show that Ucp2 deficiency impairs autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy [4].

In conclusion, Ucp2 is crucial for regulating mitochondrial function, oxidative stress, and cellular metabolism. The use of Ucp2 KO/CKO mouse models has revealed its significant roles in atherosclerosis and diabetic nephropathy, helping to understand the underlying mechanisms of these diseases and potentially providing new therapeutic targets.

References:

1. Luo, Jiang-Yun, Cheng, Chak Kwong, He, Lei, Jo, Hanjoong, Huang, Yu. 2022. Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis. In Circulation research, 131, 424-441. doi:10.1161/CIRCRESAHA.122.321187. https://pubmed.ncbi.nlm.nih.gov/35899624/

2. Nesci, Salvatore, Rubattu, Speranza. 2024. UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles. In Biomedicines, 12, . doi:10.3390/biomedicines12061307. https://pubmed.ncbi.nlm.nih.gov/38927514/

3. Toda, Chitoku, Diano, Sabrina. 2014. Mitochondrial UCP2 in the central regulation of metabolism. In Best practice & research. Clinical endocrinology & metabolism, 28, 757-64. doi:10.1016/j.beem.2014.02.006. https://pubmed.ncbi.nlm.nih.gov/25256770/

4. Yang, Qianqian, Yang, Shuqing, Liang, Yuehong, Wen, Ping, Yang, Junwei. 2023. UCP2 deficiency impairs podocyte autophagy in diabetic nephropathy. In Biochimica et biophysica acta. Molecular basis of disease, 1869, 166705. doi:10.1016/j.bbadis.2023.166705. https://pubmed.ncbi.nlm.nih.gov/37023910/