The mitochondrial protective mechanisms mediated by SGLT2i: from molecular basis to clinical implications

SGLT2 inhibitors(SGLT2i) inhibit glucose reabsorption in renal proximal tubules, promote urinary glucose excretion, and lower blood glucose. They also protect cardiovascular, renal, and nervous systems, though mechanisms remain unclear.Mitochondria are key organelles for energy metabolism, redox balance, and calcium regulation, playing a critical role in chronic disease pathogenesis and progression.SGLT2i improve mitochondrial function by enhancing quality control, modulating energy metabolism, strengthening antioxidant defenses, and maintaining calcium homeostasis.These mitochondria-centered mechanisms may underlie SGLT2i protection of cardiovascular, renal, and neurological systems. This review summarizes these effects and discusses therapeutic implications. SGLT2 inhibitors(SGLT2i) inhibit glucose reabsorption in renal proximal tubules, promote urinary glucose excretion, and lower blood glucose. They also protect cardiovascular, renal, and nervous systems, though mechanisms remain unclear. Mitochondria are key organelles for energy metabolism, redox balance, and calcium regulation, playing a critical role in chronic disease pathogenesis and progression. SGLT2i improve mitochondrial function by enhancing quality control, modulating energy metabolism, strengthening antioxidant defenses, and maintaining calcium homeostasis. These mitochondria-centered mechanisms may underlie SGLT2i protection of cardiovascular, renal, and neurological systems. This review summarizes these effects and discusses therapeutic implications. SGLT2 inhibitors have demonstrated not only potent glucose-lowering effects but also multi-system protective benefits, particularly for the cardiovascular and renal systems, as shown in large clinical trials. Growing evidence suggests these benefits may be mediated through the modulation of mitochondrial energy metabolism and oxidative stress responses. This review provides a comprehensive summary of the mechanisms by which SGLT2 inhibitors regulate mitochondrial function and discusses their potential therapeutic value in cardiovascular disease and chronic kidney disease.