The Differential Expression of Mitochondrial Function-Associated Proteins and Antioxidant Enzymes during Bovine Herpesvirus 1 Infection: A Potential Mechanism for Virus Infection-Induced Oxidative Mitochondrial Dysfunction.

Xiaotian Fu,Gaiping Zhang,Liqian Zhu,Xinyi Jiang,Xinye Chen

doi:10.1155/2019/7072917

Abstract

Reactive oxidative species (ROS) are important inflammatory mediators. Electrons escaping from the mitochondrial electron transport chain (ETC) during oxidative phosphorylation (OXPHOS) in the mitochondrial respiratory chain (RC) complexes contribute to ROS production. The cellular antioxidant enzymes are important for maintaining ROS release at the physiological levels. It has been reported that BoHV-1 infection induces overproduction of ROS and oxidative mitochondrial dysfunction in cell cultures. In this study, we found that chemical interruption of RC complexes by TTFA (an inhibitor of RC complex II), NaN3 (an inhibitor of RC complex IV), and oligomycin A (an inhibitor of ATP synthase) consistently decreased virus productive infection, suggesting that the integral processes of RC complexes are important for the virus replication. The virus infection significantly increased the expression of subunit SDHB (succinate dehydrogenase) and MTCO1 (cytochrome c oxidase subunit I), critical components of RC complexes II and IV, respectively. The expression of antioxidant enzymes including superoxide dismutase 1 (SOD1), SOD2, catalase (CAT), and glutathione peroxidase 4 (GPX4) was differentially affected following the virus infection. The protein TFAM (transcription factor A, mitochondrial) stimulated by either nuclear respiratory factor 1 (NRF1) or NRF2 is a key regulator of mitochondrial biogenesis. Interestingly, the virus infection at the late stage (at 16 h after infection) stimulated TFAM expression but decreased the levels of both NRF1 and NRF2, indicating that virus infection activated TFAM signaling independent of either NRF1 or NRF2. Overall, this study provided evidence that BoHV-1 infection altered the expression of molecules associated with RC complexes, antioxidant enzymes, and mitochondrial biogenesis-related signaling NRF1/NRF2/TFAM, which correlated with the previous report that virus infection induces ROS overproduction and mitochondrial dysfunction.

Highlights

Bovine herpesvirus type 1 (BoHV-1) is a virus of the family Herpesviridae and the subfamily Alphaherpesvirinae
We initially investigated whether chemical interruption of certain oxidative phosphorylation (OXPHOS) complexes would affect the virus productive infection by inhibitors TTFA, NaN3, and oligomycin A
Given that highly released ATP by virus-infected cells is regarded as a “danger signal” and extracellular ATP inhibits the replication of multiple viruses including HSV-1 [33], it does make sense why both BoHV-1 and HSV-1 infections decline ATP production via interruption of mitochondrial dysfunction at the late stage of infection [23, 34]

Summary

Introduction

Bovine herpesvirus type 1 (BoHV-1) is a virus of the family Herpesviridae and the subfamily Alphaherpesvirinae. Human immunodeficiency virus-1 Tat protein reduces the mitochondria size and impairs mitochondrial fission by increasing the expression levels of fission and fusion proteins dynamin-related protein 1 (Drp1) in neurons [19], vaccinia virus inhibits OXPHOS and ETC to increase ROS production during the infection of macrophages [20], and influenza A virus can translocate viral protein PB1-F2 into the mitochondria via Tom channels and thereby impairs the innate immune response mediated by mitochondria [21]. The aberrant expression of certain components in the RC complexes and antioxidant enzymes as well as the NRF1/2/TFAM signaling correlated well with a previous report that virus infection stimulates excessive ROS production and mitochondrial dysfunction. These findings add our knowledge to understand the mechanisms regarding ROS production and mitochondrial damage due to the virus infection

Materials and Methods

Results

C I: NDUFB8 C II: SDHB C IV

Discussion