title: Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling.
abstract: Mitochondria, dynamic organelles that undergo cycles of fusion and fission, are the powerhouses of eukaryotic cells and are also involved in cellular innate antiviral immunity in mammals. Mitochondrial antiviral immunity depends on activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway and the participation of a mitochondrial outer membrane adaptor protein called MAVS (mitochondrial antiviral signaling). We found that cells that lack the ability to undergo mitochondrial fusion as a result of targeted deletion of both mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) exhibited impaired induction of interferons and proinflammatory cytokines in response to viral infection, resulting in increased viral replication. In contrast, cells with null mutations in either Mfn1 or Mfn2 retained their RLR-induced antiviral responses. We also found that a reduced mitochondrial membrane potential (ΔΨ(m)) correlated with the reduced antiviral response. The dissipation in ΔΨ(m) did not affect the activation of the transcription factor interferon regulatory factor 3 downstream of MAVS, which suggests that ΔΨ(m) and MAVS are coupled at the same stage in the RLR signaling pathway. Our results provide evidence that the physiological function of mitochondria plays a key role in innate antiviral immunity.
authors.affiliation: 1Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. koshiba@kyudai.jp
authors.forename: Takumi
authors.initials: T
authors.lastname: Koshiba
authors.forename: Kai
authors.initials: K
authors.lastname: Yasukawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Kawabata
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004686:Encephalomyocarditis virus / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000502:physiology; D015398:Signal Transduction; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015850:Interleukin-6; C505371:MAVS protein, human; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016899:Interferon-beta; C547666:Dhx58 protein, mouse; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D020365:RNA Helicases