Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

Kei Fujimoto, Yun Chen, Kenneth S. Polonsky, Gerald W. Dorn

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Mutations of the pancreatic duodenal homeobox gene-1, Pdx1, cause heritable diabetes in humans and mice. A central abnormality with Pdx1 deficiency is increased death of β-cells, leading to decreased β-cell mass. We show that lentiviral suppression of Pdx1 increases death of mouse insulinoma MIN6 β-cells associated with dissipation of the mitochondrial inner membrane electrochemical gradient, ΔΨm. Preventing mitochondrial permeability transition pore opening with the cyclophilin D inhibitor cyclosporin A restored ΔΨm and rescued cell viability. Reduced β-cell mass, markers of β-cell apoptosis, necrosis, and decreased proliferation are present in Pdx1 haploinsufficient mice. Genetic ablation of the Ppif gene, encoding cyclophilin D, restored β-cell mass and decreased TUNEL and complement complex labeling without affecting β-cell proliferation. In adult mice maintained on a high-fat diet, Ppif ablation normalized fasting glucose and glucose and insulin responses to acute glucose challenge. Thus, cyclophilin D and the mitochondrial permeability transition are critical regulators of β-cell death caused by Pdx1 insufficiency.

Original languageEnglish (US)
Pages (from-to)10214-10219
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number22
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

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Permeability
Cell Survival
Glucose
Cell Death
Insulinoma
In Situ Nick-End Labeling
Mitochondrial Membranes
High Fat Diet
Cyclosporine
Fasting
Necrosis
Cell Proliferation
cyclophilin D
Insulin
Apoptosis
Mutation
Genes

Keywords

  • Apoptosis
  • Cell necrosis
  • Insulin

ASJC Scopus subject areas

  • General

Cite this

Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency. / Fujimoto, Kei; Chen, Yun; Polonsky, Kenneth S.; Dorn, Gerald W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 22, 01.06.2010, p. 10214-10219.

Research output: Contribution to journalArticle

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