Targeting cyclophilin D and the mitochondrial permeability transition enhances beta-cell survival and prevents diabetes in Pdx1 deficiency.
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 beta-cells, leading to decreased beta-cell mass. We show that lentiviral suppression of Pdx1 increases death of mouse insulinoma MIN6 beta-cells associated with dissipation of the mitochondrial inner membrane electrochemical gradient, Deltapsi(m). Preventing mitochondrial permeability transition pore opening with the cyclophilin D inhibitor cyclosporin A restored Deltapsi(m) and rescued cell viability. Reduced beta-cell mass, markers of beta-cell apoptosis, necrosis, and decreased proliferation are present in Pdx1 haploinsufficient mice. Genetic ablation of the Ppif gene, encoding cyclophilin D, restored beta-cell mass and decreased TUNEL and complement complex labeling without affecting beta-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 beta-cell death caused by Pdx1 insufficiency.
Fujimoto
Kei
K
Division of Endocrinology, Metabolism and Lipid Research, and Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Chen
Yun
Y
Polonsky
Kenneth S
KS
Dorn
Gerald W
GW
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000517:prevention & control; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D000081406:Peptidyl-Prolyl Isomerase F; D018398:Homeodomain Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D016572:Cyclosporine; D021983:Cyclophilins