Targeting Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs): A Novel Therapeutic Strategy for Diabetic...

The pathogenesis of diabetes mellitus and its complications involves multiple factors and complex mechanisms. Currently, clinical treatment options remain limited, posing an ongoing and severe challenge to global public health. Therefore, in-depth research and understanding are urgently needed to advance the development of therapeutic strategies. Extensive studies have indicated that the endoplasmic reticulum (ER) and mitochondria are key organelles driving the occurrence and progression of diabetes mellitus and its complications. Notably, the mitochondria-associated endoplasmic reticulum membranes (MAMs), serving as a physical and functional bridge connecting the ER and mitochondria, play a critical role in maintaining organelle functional homeostasis, which underscores the importance of inter-organelle communication. This review systematically summarizes the integrated structure and regulatory mechanisms of MAMs, as well as their physiological functions in mediating inter-organelle signal transduction and material exchange. Furthermore, it elaborates in detail on the diverse pathogenic roles of MAMs dysfunction in diabetes mellitus and its complications, with a focus on its involvement in calcium signaling, lipid synthesis and transport, mitochondrial dynamics, cellular stress, and cell death. In addition, this review specifically points out that multi-component and multi-target holistic regulatory strategies exhibit unique potential in restoring MAMs homeostasis, thereby providing novel perspectives and potential preclinical intervention approaches for the "holistic regulation" treatment of diabetes complications. In conclusion, clarifying the role of MAMs in diabetes mellitus and its complications is expected to lay an important theoretical foundation for the development of preclinical therapeutic strategies, although significant challenges remain for clinical translation, including tissue-specific targeting, safety, and the lack of validated biomarkers.