Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure

BACKGROUND: One of the most common side effects of the immunosuppressive drug tacrolimus (FK506) is the increased risk of new-onset diabetes mellitus. However, the molecular mechanisms underlying this association have not been fully clarified. METHODS: We studied the effects of the therapeutic dose of tacrolimus on mitochondrial fitness in beta-cells. RESULTS: We demonstrate that tacrolimus impairs glucose-stimulated insulin secretion (GSIS) in beta-cells through a previously unidentified mechanism. Indeed, tacrolimus causes a decrease in mitochondrial Ca(2+) uptake, accompanied by altered mitochondrial respiration and reduced ATP production, eventually leading to impaired GSIS. CONCLUSION: Our observations individuate a new fundamental mechanism responsible for the augmented incidence of diabetes following tacrolimus treatment. Indeed, this drug alters Ca(2+) fluxes in mitochondria, thereby compromising metabolism-secretion coupling in beta-cells.