| Targeting cyclophilin D and the mitochondrial permeability transition enhances beta-cell survival and prevents diabetes in Pdx1 deficiency. | |
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MedLine Citation:
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PMID: 20479245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Kei Fujimoto; Yun Chen; Kenneth S Polonsky; Gerald W Dorn |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-05-17 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-10 Completed Date: 2010-06-29 Revised Date: 2013-03-08 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 10214-9 Citation Subset: IM |
Affiliation:
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Division of Endocrinology, Metabolism and Lipid Research, and Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Newborn Apoptosis / drug effects Cell Line Cell Survival / drug effects Cyclophilins / antagonists & inhibitors*, genetics Cyclosporine / pharmacology Diabetes Mellitus, Type 1 / genetics, prevention & control Homeodomain Proteins / genetics Humans Insulin-Secreting Cells / cytology, drug effects*, metabolism* Membrane Potential, Mitochondrial / drug effects Mice Mice, Knockout Microscopy, Electron, Transmission Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*, genetics Necrosis Trans-Activators / deficiency*, genetics |
| Grant Support | |
ID/Acronym/Agency:
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GP60 DK-20579/DK/NIDDK NIH HHS; P30 DK052574/DK/NIDDK NIH HHS; R01 DK031842/DK/NIDDK NIH HHS; R01 HL059888/HL/NHLBI NIH HHS; R01 HL059888-12/HL/NHLBI NIH HHS; R01 HL059888-13/HL/NHLBI NIH HHS; UL1 RR024992/RR/NCRR NIH HHS; UL1 TR000448/TR/NCATS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/Mitochondrial Membrane Transport Proteins; 0/Trans-Activators; 0/mitochondrial permeability transition pore; 0/pancreatic and duodenal homeobox 1 protein; 59865-13-3/Cyclosporine; EC 5.2.1.-/Cyclophilins; EC 5.2.1.8/cyclophilin D |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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