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

Authors
  • Lombardi, Angela1
  • Trimarco, Bruno2
  • Iaccarino, Guido3
  • Santulli, Gaetano1, 2
  • 1 Albert Einstein College of Medicine, Department of Medicine, New York, NY, USA , New York (United States)
  • 2 “Federico II” University of Naples, Department of Advanced Biomedical Sciences, Naples, Italy , Naples (Italy)
  • 3 University of Salerno, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, Fisciano, Italy , Fisciano (Italy)
Type
Published Article
Journal
Cell Communication and Signaling
Publisher
BioMed Central
Publication Date
Nov 13, 2017
Volume
15
Issue
1
Identifiers
DOI: 10.1186/s12964-017-0203-0
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundOne 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.MethodsWe studied the effects of the therapeutic dose of tacrolimus on mitochondrial fitness in beta-cells.ResultsWe 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.ConclusionOur 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.

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