title: Mitochondrial DNA stress primes the antiviral innate immune response.
abstract: Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: A Phillip
authors: AP
authors: West
authors: Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: William
authors: W
authors: Khoury-Hanold
authors: Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Matthew
authors: M
authors: Staron
authors: Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Michal C
authors: MC
authors: Tal
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Cristiana M
authors: CM
authors: Pineda
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Sabine M
authors: SM
authors: Lang
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Megan
authors: M
authors: Bestwick
authors: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors: Brett A
authors: BA
authors: Duguay
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Nuno
authors: N
authors: Raimundo
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Donna A
authors: DA
authors: MacDuff
authors: 1] Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
authors: Susan M
authors: SM
authors: Kaech
authors: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors: James R
authors: JR
authors: Smiley
authors: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Robert E
authors: RE
authors: Means
authors: 1] Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
authors: Akiko
authors: A
authors: Iwasaki
authors: 1] Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors: Gerald S
authors: GS
authors: Shadel
mesh_terms: D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009713:Nucleotidyltransferases / Q000378:metabolism; D013312:Stress, Physiological; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C081930:Tfam protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
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