The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells

Authors

Hanjun Guan, University of Kentucky
K. Martin Chow, University of Kentucky
Eunsuk Song, University of KentuckyFollow
Nirmal Verma, University of KentuckyFollow
Florin Despa, University of KentuckyFollow
Louis B. Hersh, University of KentuckyFollow

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.

Document Type

Article

Publication Date

7-20-2015

Notes/Citation Information

Published in PLOS One, v. 10, no. 7, article e0133263, p. 1-16.

© 2015 Guan et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pone.0133263

Funding Information

This work was funded by National Institutes on Drug Abuse (http://www.drugabuse.gov/; grant RO1DA02243; LBH), National Institutes of General Medical Sciences (http://www.nigms.nih.gov; grant P2ORR020171; LBH), National Institutes Heart Lung and Blood (http://www.nhlbi.nih.gov; grant R01-HL118474; FD), and National Science Foundation (http://www.nsf.gov; grant CBET 1133339; FD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Guan, Hanjun; Chow, K. Martin; Song, Eunsuk; Verma, Nirmal; Despa, Florin; and Hersh, Louis B., "The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells" (2015). Molecular and Cellular Biochemistry Faculty Publications. 71.
https://uknowledge.uky.edu/biochem_facpub/71