PACS2, also known as phosphofurin acidic cluster sorting protein 2, plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy [2]. It is also involved in pathways related to fatty acid oxidation and is associated with mitochondria-associated endoplasmic reticulum membranes (MAMs) [3,4]. Genetic models, such as mouse models, are valuable for studying PACS2.

In a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), PACS2 deletion reversed treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues, indicating that the PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in diabetic cardiomyopathy by regulating cardiomyocyte mitochondrial function [1]. In diabetic mice, lacking PACS2 improved vascular leakage and glomerulosclerosis under high-fat diet, suggesting PACS2 participates in renal vascular hyperpermeability and glomerulosclerosis by regulating the fatty acid oxidation (FAO) of diabetic mice [4]. Cardiac-specific knockout of Pacs2 in mice exacerbated mitophagy inhibition, cardiomyocyte injury, and right cardiac dysfunction induced by hypobaric hypoxia, while conditional knock-in recovered the right cardiac impairment, showing PACS2 is essential for protecting cardiomyocytes through ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism [5].

In conclusion, PACS2 is crucial for multiple cellular functions including maintaining mitochondrial function, regulating calcium flux, and controlling autophagy-related processes. Mouse models, especially KO/CKO mouse models, have significantly contributed to understanding PACS2's role in diseases such as diabetic cardiomyopathy, diabetic nephropathy, and hypobaric hypoxia-induced cardiac dysfunction, providing insights into potential therapeutic targets for these conditions.

References:

1. Xiang, Hong, Lyu, Qi, Chen, Shuhua, Yang, Xiaoping, Lu, Hongwei. 2024. PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy. In Cardiovascular diabetology, 23, 432. doi:10.1186/s12933-024-02514-6. https://pubmed.ncbi.nlm.nih.gov/39633391/

2. Zbikowski, Arkadiusz, Kowalczyk, Tomasz, Kasparek, Petr, Cysewski, Dominik, Łukasiewicz, Kacper. 2024. Understanding PACS2 syndrome's pathomechanism by studying E209K and E211K mutations. In Mammalian genome : official journal of the International Mammalian Genome Society, , . doi:10.1007/s00335-024-10098-5. https://pubmed.ncbi.nlm.nih.gov/39738582/

3. Mao, Hui, Chen, Wei, Chen, Linxi, Li, Lanfang. 2022. Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases. In Biochemical pharmacology, 199, 115011. doi:10.1016/j.bcp.2022.115011. https://pubmed.ncbi.nlm.nih.gov/35314166/

4. Shu, Zhihao, Chen, Shuhua, Xiang, Hong, Chen, Alex F, Lu, Hongwei. 2022. AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice. In Frontiers in pharmacology, 13, 876937. doi:10.3389/fphar.2022.876937. https://pubmed.ncbi.nlm.nih.gov/35865947/

5. Yang, Jie, Sun, Mengjia, Chen, Renzheng, Wang, Xuhong, Huang, Lan. 2023. Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia. In iScience, 26, 106328. doi:10.1016/j.isci.2023.106328. https://pubmed.ncbi.nlm.nih.gov/36968068/