Ucp2, an uncoupling protein homolog to UCP1, is a mitochondrial anion carrier protein located in the mitochondrial inner membrane [2,3,4]. It uncouples oxidative phosphorylation from ATP production by dissipating the proton gradient across the mitochondrial inner membrane, regulating mitochondrial ATP production and the generation of reactive oxygen species (ROS) [2,4]. Ucp2 is involved in multiple pathways, such as those related to oxidative stress, cellular metabolism, cell proliferation, and cell death [3].

In endothelial cells, EC-specific Ucp2 knockout mice studies revealed that Ucp2 is a mechanosensitive gene under the control of fluid shear stress and KLF2. Ucp2 deficiency promotes atherogenesis and collagen production, while its overexpression inhibits carotid atherosclerotic plaque formation, indicating its crucial role in endothelial pro-inflammatory response and atherogenesis [1]. In podocytes, podocyte-specific Ucp2-KO mice showed that Ucp2 deficiency impairs autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy, suggesting Ucp2 protects against hyperglycemia-induced podocyte injury by promoting autophagy [5].

In conclusion, Ucp2 plays essential roles in regulating mitochondrial function, oxidative stress, and cellular metabolism. The use of Ucp2 KO/CKO mouse models has significantly contributed to understanding its roles in diseases like atherosclerosis and diabetic nephropathy, providing insights into potential therapeutic strategies targeting Ucp2 for these conditions.