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Mitochondrial DNA Stress Primes The Antiviral Innate Immune Response

A. West, William Khoury-Hanold, Matthew M. Staron, M. Tal, C. M. Pineda, S. Lang, Megan L. Bestwick, Brett A. Duguay, N. Raimundo, D. MacDuff, S. Kaech, J. Smiley, R. Means, A. Iwasaki, G. Shadel
Published 2014 · Biology, Medicine

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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.
This paper references
10.1073/PNAS.83.21.8122
Eukaryotic transient-expression system based on recombinant vaccinia virus that synthesizes bacteriophage T7 RNA polymerase.
T. Fuerst (1986)
A mouse model for studies of mucosal immunity to vaginal infection by herpes simplex virus type 2.
M. Parr (1994)
10.1038/NG0398-231
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
N. Larsson (1998)
10.1128/JVI.72.9.7563-7568.1998
Incorporation of the Green Fluorescent Protein into the Herpes Simplex Virus Type 1 Capsid
P. Desai (1998)
10.1006/VIRO.2000.0736
Vesicular stomatitis virus glycoprotein containing the entire green fluorescent protein on its cytoplasmic domain is incorporated efficiently into virus particles.
K. Dalton (2001)
Vesicular stomatitis virus glycoprotein containing the entire green fluorescent protein on its cytoplasmic domain is incorporated efficiently into virus particles. Virology
KP Dalton (2001)
10.2144/03342MT01
TM4: a free, open-source system for microarray data management and analysis.
A. Saeed (2003)
10.1097/01.bor.0000135453.70424.1b
Interferon-α in systemic lupus erythematosus
M. Crow (2004)
10.1146/ANNUREV.GENET.39.110304.095751
A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.
D. Wallace (2005)
10.1093/nar/gkl703
Alterations to the expression level of mitochondrial transcription factor A, TFAM, modify the mode of mitochondrial DNA replication in cultured human cells
J. Pohjoismäki (2006)
10.1016/J.IMMUNI.2005.12.003
Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.
D. Stetson (2006)
10.1158/0008-5472.CAN-07-1019
Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells.
N. Khodarev (2007)
10.1038/nprot.2006.461
Production of dissociated sensory neuron cultures and considerations for their use in studying neuronal function and plasticity
S. Malin (2007)
10.1038/sj.embor.7400878
Herpes simplex virus eliminates host mitochondrial DNA
H. Saffran (2007)
10.1146/ANNUREV.BIOCHEM.76.052305.091720
Mitochondrial-nuclear communications.
M. Ryan (2007)
10.1128/JVI.02198-07
Epstein-Barr Virus Immediate-Early Protein Zta Co-Opts Mitochondrial Single-Stranded DNA Binding Protein To Promote Viral and Inhibit Mitochondrial DNA Replication
Andreas Wiedmer (2008)
10.1093/nar/gkm1169
EXOG, a novel paralog of Endonuclease G in higher eukaryotes
I. Cymerman (2008)
10.1002/9780471729259.mc15a01s8
Lymphocytic Choriomeningitis Virus (LCMV): Propagation, Quantitation, and Storage
R. Welsh (2008)
10.1038/nature07432
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
(2008)
10.1016/J.JVIROMET.2007.08.025
Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo.
M. McCausland (2008)
10.1093/hmg/ddp281
Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA.
A. Malena (2009)
10.1128/JVI.02087-08
Herpes Simplex Virus UL12.5 Targets Mitochondria through a Mitochondrial Localization Sequence Proximal to the N Terminus
Jennifer A. Corcoran (2009)
10.1186/1756-0500-2-243
Crude subcellular fractionation of cultured mammalian cell lines
P. Holden (2009)
10.1073/pnas.0807694106
Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
M. C. Tal (2009)
10.1002/iub.282
Functional organization of mammalian mitochondrial DNA in nucleoids: History, recent developments, and future challenges
J. N. Spelbrink (2009)
10.1073/pnas.1003428107
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
F. Weinberg (2010)
10.1038/nri2975
Mitochondria in innate immune responses
A. P. West (2011)
10.1016/j.immuni.2011.08.016
Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection.
Heather D. Marshall (2011)
10.1016/j.coviro.2011.10.008
Interferon-stimulated genes and their antiviral effector functions
J. Schoggins (2011)
10.1186/ar3317
Underexpression of mitochondrial-DNA encoded ATP synthesis-related genes and DNA repair genes in systemic lupus erythematosus
Hooi-Ming Lee (2011)
10.1111/j.1600-0897.2010.00908.x
Placental Viral Infection Sensitizes to Endotoxin‐Induced Pre‐Term Labor: A Double Hit Hypothesis
I. Cardenas (2011)
10.1016/j.yexcr.2010.10.008
Human mitochondrial transcription factor A is required for the segregation of mitochondrial DNA in cultured cells.
K. Kasashima (2011)
10.3390/ijms13078853
Leukocyte Mitochondrial DNA Alteration in Systemic Lupus Erythematosus and Its Relevance to the Susceptibility to Lupus Nephritis
Hui-ting Lee (2012)
10.1016/j.ajpath.2011.10.003
Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APC(Min/+) mice.
D. Woo (2012)
10.1016/j.cell.2011.12.027
Mitochondrial Stress Engages E2F1 Apoptotic Signaling to Cause Deafness
N. Raimundo (2012)
10.1016/j.immuni.2012.01.009
Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
K. Shimada (2012)
10.1038/nrc3365
Mitochondria and cancer
D. Wallace (2012)
10.1016/j.chom.2012.07.013
A neuron-specific role for autophagy in antiviral defense against herpes simplex virus.
Brian Yordy (2012)
10.1038/nature11522
A vaccine strategy protects against genital herpes by establishing local memory T cells
Haina Shin (2012)
10.1073/pnas.1301951110
Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c
Reiko Ban-Ishihara (2013)
10.4049/jimmunol.1203162
Molecular Basis of DNA Recognition in the Immune System
M. Atianand (2013)
10.1073/pnas.1303275110
Efficient influenza A virus replication in the respiratory tract requires signals from TLR7 and RIG-I
I. K. Pang (2013)
10.1126/science.1232458
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
(2013)
10.1128/JVI.02306-13
Mitochondrial Nucleases ENDOG and EXOG Participate in Mitochondrial DNA Depletion Initiated by Herpes Simplex Virus 1 UL12.5
Brett A Duguay (2013)
10.1016/j.immuni.2013.05.007
Cytosolic Sensing of Viruses
D. Goubau (2013)
10.1093/nar/gks1215
INTERFEROME v2.0: an updated database of annotated interferon-regulated genes
I. Rusinova (2012)
10.1128/JVI.03129-13
Elimination of Mitochondrial DNA Is Not Required for Herpes Simplex Virus 1 Replication
Brett A Duguay (2013)
10.1016/j.molcel.2014.03.040
The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling.
Xin Cai (2014)
10.1016/j.exger.2014.03.027
In D-loop: 40years of mitochondrial 7S DNA
T. Nicholls (2014)
10.4049/jimmunol.1400737
TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner
Andrea Ablasser (2014)
Error bars indicate ± s.e.m. of triplicates and are representative of three independent experiments. ***=p<0



This paper is referenced by
10.1016/j.jbc.2021.100904
Mitochondrial metabolism regulates macrophage biology
Yafang Wang (2021)
10.1016/j.apsb.2021.11.003
Mitochondrial complex I as a therapeutic target for Alzheimer’s disease
E. Trushina (2021)
10.15252/embj.2021108293
Nuclear cGAS: guard or prisoner?
C. C. de Oliveira Mann (2021)
10.3389/fimmu.2021.769543
Running With Scissors: Evolutionary Conflicts Between Viral Proteases and the Host Immune System
(2021)
10.1371/journal.ppat.1009841
Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase
Hiroki Sato (2021)
10.3390/cells10102700
A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment
F. Hofer (2021)
10.1016/j.arr.2021.101405
Ageing mechanisms that contribute to tissue remodeling in lung disease
M. Schuliga (2021)
10.1002/mds.28475
Nuclear Genes Associated with Mitochondrial DNA Processes as Contributors to Parkinson's Disease Risk.
Amica C Müller-Nedebock (2021)
10.3389/fcell.2021.655819
Genetic Imaging of Neuroinflammation in Parkinson’s Disease: Recent Advancements
Longping Yao (2021)
10.4239/wjd.v12.i10.1655
Role of nucleic acid sensing in the pathogenesis of type 1 diabetes
Darshan Badal (2021)
10.1089/rej.2021.0062
Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer's Disease.
James W Larrick (2021)
10.1101/2021.04.02.438201
Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A
A. Lepelley (2021)
10.1038/s41385-021-00424-4
Candida vaginitis: the importance of mitochondria and type I interferon signalling.
N. Papon (2021)
10.1002/9781119597896.ch3
The Role of Mitochondria in Age‐Related Sarcopenia
L. Ferrucci (2021)
10.3390/cells10112898
Molecular Mechanisms of mtDNA-Mediated Inflammation
(2021)
10.1016/j.molcel.2021.04.005
RNA reports breaking news from mitochondria.
Nimesha Tadepalle (2021)
10.3390/cells10030537
Cell Death and Inflammation: The Role of Mitochondria in Health and Disease
A. Picca (2021)
10.1038/s41586-021-03994-2
KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements.
Shang-Min Zhang (2021)
10.1016/j.bioactmat.2020.12.024
Alda-1 treatment promotes the therapeutic effect of mitochondrial transplantation for myocardial ischemia-reperfusion injury☆
Xiaolei Sun (2021)
10.1002/iid3.452
Activation of the cGAS–STING signaling pathway in adenomyosis patients
Yun Lin (2021)
10.1038/s41423-021-00673-0
VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release.
W. He (2021)
10.1101/gr.269381.120
Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.
Stephanie Y. Yang (2021)
10.1016/j.celrep.2021.108775
Disruption of DNA polymerase ζ engages an innate immune response.
S. K. Martin (2021)
10.15252/embj.2020106065
5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING
J. Tian (2021)
10.1111/acel.13329
NAD+ supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy
Beimeng Yang (2021)
10.1038/s41586-021-03542-y
The role of retrotransposable elements in ageing and age-associated diseases.
V. Gorbunova (2021)
10.1007/s11481-021-10031-6
STING/NF-κB/IL-6-Mediated Inflammation in Microglia Contributes to Spared Nerve Injury (SNI)-Induced Pain Initiation.
Jia Sun (2021)
10.1016/j.bbagen.2021.129871
Hidden phenotypes of PINK1/Parkin knockout mice.
Swagatika Paul (2021)
10.3389/fcell.2021.720490
Metabolism and Innate Immunity Meet at the Mitochondria
Amir Bahat (2021)
10.1038/s43587-021-00098-4
Autophagy in healthy aging and disease
Yahyah Aman (2021)
10.3389/fcell.2021.664896
Mechanism of Mitophagy and Its Role in Sepsis Induced Organ Dysfunction: A Review
Cheng-long Zhu (2021)
10.1016/j.dnarep.2021.103134
Perspectives on formaldehyde dysregulation: Mitochondrial DNA damage and repair in mammalian cells.
C. Nadalutti (2021)
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