Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication.
Redox homeostasis is an important host factor determining the outcome of infectious disease. Enterovirus 71 (EV71) infection has become an important endemic disease in Southeast Asia and China. We have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. The detailed mechanism for reactive oxygen species (ROS) generation in infected cells remains elusive. In the current study, we demonstrate that mitochondria were a major ROS source in EV71-infected cells. Mitochondria in productively infected cells underwent morphologic changes and exhibited functional anomalies, such as a decrease in mitochondrial electrochemical potential ΔΨ(m) and an increase in oligomycin-insensitive oxygen consumption. Respiratory control ratio of mitochondria from infected cells was significantly lower than that of normal cells. The total adenine nucleotide pool and ATP content of EV71-infected cells significantly diminished. However, there appeared to be a compensatory increase in mitochondrial mass. Treatment with mito-TEMPO reduced eIF2α phosphorylation and viral replication, suggesting that mitochondrial ROS act to promote viral replication. It is plausible that EV71 infection induces mitochondrial ROS generation, which is essential to viral replication, at the sacrifice of efficient energy production, and that infected cells up-regulate biogenesis of mitochondria to compensate for their functional defect.
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan; Metabolomics Core Laboratory, Chang Gung University, Tao-Yuan, Taiwan.
Mei-Ling
ML
Cheng
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Shiue-Fen
SF
Weng
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Chih-Hao
CH
Kuo
Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Office of Research and Development, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
Hung-Yao
HY
Ho
D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002681:China; D003497:Cyclic N-Oxides / Q000494:pharmacology; D029821:Enterovirus A, Human / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; C003959:TEMPO