Sigmar1, also known as the sigma-1 receptor, is a multifunctional inter-organelle signaling chaperone protein [1]. It is ubiquitously expressed and plays diverse roles in cellular survival. Sigmar1 is enriched at the mitochondria-associated endoplasmic reticulum membrane (MAM), and is involved in numerous cellular functions such as ion channel regulation, protein quality control, and autophagy activation. It also participates in lipid metabolism, mitochondrial function, and endoplasmic reticulum-mitochondrial communication [1,2]. Genetic models, like KO/CKO mouse models, are valuable tools for studying Sigmar1.

In Sigmar1 knockout mice, mitochondrial clearance was impaired without altering the PINK1-PRKN/Parkin signaling, and autophagosome-lysosome fusion was partially compromised, leading to the accumulation of autophagosome markers [5]. In a methamphetamine-induced hypertension mouse model, Sigmar1 knockout mice showed higher blood pressure and more collagen deposition around vessels compared to wild-type mice, suggesting Sigmar1 is involved in methamphetamine-induced hypertension and vascular fibrosis by blocking the TGF-β/Smad2/3 signaling pathway [3]. Also, mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model, indicating Sigmar1 is a negative regulator of osteoclastogenesis [4].

In conclusion, Sigmar1 is essential for maintaining normal cellular functions such as autophagy, mitochondrial function, and cellular homeostasis. The study of Sigmar1 KO/CKO mouse models has revealed its significance in neurodegenerative diseases, cardiovascular diseases, and osteoporosis. Understanding Sigmar1's functions can provide potential therapeutic strategies for these diseases.