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

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.

Bovine Herpesvirus 1 Productive Infection Led to Inactivation of Nrf2 Signaling through Diverse Approaches

“…Nrf2 also regulates multiple cellular processes including cell differentiation, proliferation, and inflammation [36], which may be closely related to virus pathogenesis. BoHV-1 infection significantly reduces Nrf2 expression which is inconsistent with the report that virus infection enhances ROS production in cell cultures [4, 15, 18]. Here, we raised questions of whether and how the virus infection inhibits the Nrf2 signaling pathway.…”

“…We have recently reported that the steady-state protein levels of Nrf2 are significantly reduced during BoHV-1 productive infection at the later stage [18]; however, whether the Nrf2 signaling pathway is consequently inhibited remains unknown. In order to evaluate the activity of Nrf2 signaling, we first detected the protein levels of HO-1 and NQO1, the canonical downstream targets regulated by Nrf2 signaling.…”

“…It is well established that the redox-sensitive transcription factor, NF-E2-related factor 2 (Nrf2), and Nrf2 antioxidant response pathways provide the primary cellular defenses against the oxidative stress [16, 17]. We have recently reported that BoHV-1 infection in MDBK cells inhibited Nrf2 expression [18].…”

“…Though we have recently demonstrated that BoHV-1 infection destabilized Nrf2 protein expression [18], the status of Nrf2-regulated antioxidant signaling and the mechanisms underlying Nrf2 depletion in the virus-infected cells have yet to be determined. Here, for the first time, we demonstrated that the virus infection suppressed the Nrf2 signaling pathway through multiple approaches, including inhibiting of the Nrf2 accumulation in the nucleus, inducing the relocalization of nucleus Nrf2 to form dot-like structures and the deacetylation of nucleus Nrf2, and manipulating the DJ-1/KEAP1 complex to promote the degradation of Nrf2 via the ubiquitin proteasome pathway.…”

Candesartan could ameliorate the COVID-19 cytokine storm

“…Within our 210-gene list, a genetic variant of IFITM3 has been recently associated with age-dependent COVID-19 severity [ 142 ], and ADAP2 has been proposed to participate in Alzheimer’s disease progression [ 143 ]. Downregulation of SOD2 , a gene with antiaging effects that ameliorates DNA damage and protects against cellular senescence [ 144 ] is normalized by ARB treatment in a rodent model of Alzheimer’s disease [ 145 ].…”