Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects β-cells from virally mediated lysis. J Biol Chem 2020 Dec 04;295(49):16655-16664
Date
09/26/2020Pubmed ID
32972972Pubmed Central ID
PMC7864063DOI
10.1074/jbc.RA120.014851Scopus ID
2-s2.0-85097570380 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide-dependent manner.
Author List
Stafford JD, Shaheen ZR, Yeo CT, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cells, Cultured
Encephalomyocarditis virus
Female
Insulin-Secreting Cells
Interferon-beta
Male
Mice
Mice, Inbred C57BL
Mitochondria
Myxovirus Resistance Proteins
Nitric Oxide
Nitric Oxide Donors
Oxidative Stress
Poly I-C
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Unfolded Protein Response
Up-Regulation
Virus Replication
