TY - JOUR
T1 - Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency
AU - Fujimoto, Kei
AU - Chen, Yun
AU - Polonsky, Kenneth S.
AU - Dorn, Gerald W.
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cell necrosis
KW - Insulin
UR - http://www.scopus.com/inward/record.url?scp=77953389460&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914209107
DO - 10.1073/pnas.0914209107
M3 - Article
C2 - 20479245
AN - SCOPUS:77953389460
SN - 0027-8424
VL - 107
SP - 10214
EP - 10219
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -