SGLT2 inhibitors as modulators of mitochondrial ion transport and ER-mitochondria cross talk in diabetic...

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus and a leading contributor to heart failure. A central feature of DCM is the disruption of mitochondrial bioenergetics and calcium homeostasis, processes that are tightly regulated through mitochondria-associated endoplasmic reticulum membranes (MAMs). These endoplasmic reticulum (ER)-mitochondria contact sites coordinate mitochondrial ion transport systems, including the mitochondrial calcium uniporter, Na⁺/Ca²⁺ exchanger, and potassium channels, which collectively govern mitochondrial metabolism, redox balance, and cell survival. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, have recently demonstrated robust cardioprotective effects independent of glycemic control. Emerging evidence suggests that these benefits are partly mediated through the regulation of mitochondrial function and ER stress signaling. In this review, we discuss how SGLT2 inhibitors-particularly empagliflozin, canagliflozin, and dapagliflozin-modulate mitochondrial ion homeostasis, mitochondrial dynamics, and mitophagy in diabetic hearts. We further highlight their potential role in stabilizing ER-mitochondria communication by attenuating unfolded protein response signaling and restoring calcium balance at MAM interfaces. Finally, we explore the emerging concept that combining SGLT2 inhibitors with exercise may synergistically improve mitochondrial quality control and ER-mitochondria coupling, representing a promising pharmaco-lifestyle strategy for diabetic cardiomyopathy. Understanding how mitochondrial ion transport and organelle cross talk are modulated by SGLT2 inhibitors may provide new mechanistic insights and therapeutic opportunities for cardiometabolic diseases.