title: The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells.
abstract: Amyloid formation and mitochondrial dysfunction are characteristics of type 2 diabetes. The major peptide constituent of the amyloid deposits in type 2 diabetes is islet amyloid polypeptide (IAPP). In this study, we found that pitrilysin, a zinc metallopeptidase of the inverzincin family, degrades monomeric, but not oligomeric, islet amyloid polypeptide in vitro. In insulinoma cells when pitrilysin expression was decreased to 5% of normal levels, there was a 60% increase in islet amyloid polypeptide-induced apoptosis. In contrast, overexpression of pitrilysin protects insulinoma cells from human islet amyloid polypeptide-induced apoptosis. Since pitrilysin is a mitochondrial protein, we used immunofluorescence staining of pancreases from human IAPP transgenic mice and Western blot analysis of IAPP in isolated mitochondria from insulinoma cells to provide evidence for a putative intramitochondrial pool of IAPP. These results suggest that pitrilysin regulates islet amyloid polypeptide in beta cells and suggest the presence of an intramitochondrial pool of islet amyloid polypeptide involved in beta-cell apoptosis.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, KY, 40536-0509, United States of America.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, KY, 40536-0509, United States of America.
authors.forename: K Martin
authors.initials: KM
authors.lastname: Chow
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, KY, 40536-0509, United States of America.
authors.forename: Eunsuk
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky, 459 Wethington Bldg., 800 Rose St., Lexington, KY, 40536-0200, United States of America.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Verma
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky, 459 Wethington Bldg., 800 Rose St., Lexington, KY, 40536-0200, United States of America.
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Biomedical Biological Sciences Research Building, 741 South Limestone St., Lexington, KY, 40536-0509, United States of America.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D051381:Rats
chemical_list: D058228:Islet Amyloid Polypeptide; D008666:Metalloendopeptidases; C046583:pitrilysin