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Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure
Authors:Angela Lombardi  Bruno Trimarco  Guido Iaccarino  Gaetano Santulli
Affiliation:1.Department of Medicine,Albert Einstein College of Medicine,New York,USA;2.Department of Advanced Biomedical Sciences,“Federico II” University of Naples,Naples,Italy;3.Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”,University of Salerno,Fisciano,Italy
Abstract:

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 Ca2+ 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 Ca2+ fluxes in mitochondria, thereby compromising metabolism-secretion coupling in beta-cells.
Keywords:
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