Faculty Collaboration Database

Pancreatic β-cells detoxify H₂O₂ through the peroxiredoxin/thioredoxin antioxidant system. J Biol Chem 2019 Mar 29;294(13):4843-4853

Date

01/20/2019

Pubmed ID

30659092

Pubmed Central ID

PMC6442057

DOI

10.1074/jbc.RA118.006219

Scopus ID

2-s2.0-85063968215 (requires institutional sign-in at Scopus site)   59 Citations

Abstract

Oxidative stress is thought to promote pancreatic β-cell dysfunction and contribute to both type 1 and type 2 diabetes. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, are mediators of oxidative stress that arise largely from electron leakage during oxidative phosphorylation. Reports that β-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which β-cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of β-cells in the control of metabolic homeostasis and organismal survival through exquisite coupling of oxidative phosphorylation, a prominent ROS-producing pathway, to insulin secretion. Using glucose oxidase to deliver H₂O₂ continuously over time and Amplex Red to measure extracellular H₂O₂ concentration, we found here that β-cells can remove micromolar levels of this oxidant. This detoxification pathway utilizes the peroxiredoxin/thioredoxin antioxidant system, as selective chemical inhibition or siRNA-mediated depletion of thioredoxin reductase sensitized β-cells to continuously generated H₂O₂ In contrast, when delivered as a bolus, H₂O₂ induced the DNA damage response, depleted cellular energy stores, and decreased β-cell viability independently of thioredoxin reductase inhibition. These findings show that β-cells have the capacity to detoxify micromolar levels of H₂O₂ through a thioredoxin reductase-dependent mechanism and are not as sensitive to oxidative damage as previously thought.

Author List

Stancill JS, Broniowska KA, Oleson BJ, Naatz A, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Survival
DNA Damage
Hydrogen Peroxide
Insulin-Secreting Cells
Male
Oxidation-Reduction
Peroxiredoxins
Rats
Rats, Sprague-Dawley
Thioredoxin-Disulfide Reductase
Thioredoxins