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

Angela Lombardi, Bruno Trimarco, Guido Iaccarino, Gaetano Santulli

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article number47
JournalCell Communication and Signaling
Volume15
Issue number1
DOIs
StatePublished - Nov 13 2017

Fingerprint

Tacrolimus
Calcium
Medical problems
Insulin
Glucose
Mitochondria
Therapeutic Uses
Immunosuppressive Agents
Drug-Related Side Effects and Adverse Reactions
Metabolism
Pharmaceutical Preparations
Diabetes Mellitus
Respiration
Adenosine Triphosphate
Fluxes
Incidence

Keywords

  • ATP
  • Ca leak
  • Diabetes
  • Immunosuppressive regimen
  • Insulin release
  • Mitochondrial calcium

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure. / Lombardi, Angela; Trimarco, Bruno; Iaccarino, Guido; Santulli, Gaetano.

In: Cell Communication and Signaling, Vol. 15, No. 1, 47, 13.11.2017.

Research output: Contribution to journalArticle

Lombardi, Angela ; Trimarco, Bruno ; Iaccarino, Guido ; Santulli, Gaetano. / Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure. In: Cell Communication and Signaling. 2017 ; Vol. 15, No. 1.
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