A Small-Molecule Mitofusin 1 Agonist Enhances Islet Survival Under Hypoxic Conditions In Vitro and Improves Transplantation Outcomes

<b>Background</b>: Hypoxia-induced oxidative stress compromises the survival and function of transplanted islets, contributing to high rates of islet transplantation failure. <b>Methods</b>: This study investigated the small-molecule mitochondrial fusion agonist S89, which specifically activates mitofusin 1 (MFN1). We assessed its protective effects against hypoxia-induced oxidative stress and apoptosis in pancreatic β-cells. <b>Results</b>: In mouse insulinoma cells (Min6), S89 enhanced cell viability by promoting mitochondrial fusion to inhibit mitochondrial reactive oxygen species (mtROS) overaccumulation (S89 reduced mtROS by approximately 30%) and attenuated mitochondrial lipid peroxidation; furthermore, it suppressed hypoxia-induced apoptosis via downregulation of the BAX/BCL-2 ratio, thus protecting the cells from hypoxia-induced oxidative damage. Notably, S89 significantly potentiated glucose-stimulated insulin secretion (GSIS) in both the Min6 β-cell line and primary mouse islets. Critically, S89 pretreatment enhanced hypoxia resistance in islets and significantly increased graft survival upon transplantation into streptozotocin (STZ)-induced type 1 diabetic (T1D) mice, maintaining prolonged blood glucose homeostasis. <b>Conclusions</b>: These findings demonstrate that S89 protects β-cells from hypoxic injury, indicating its efficacy as a therapeutic approach for improving islet transplantation outcomes.