Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response

By A. West, William Khoury-Hanold, Matthew M. Staron, M. C. Tal, C. Pineda, S. Lang, Megan L. Bestwick, Brett A. Duguay, N. Raimundo, Donna A. MacDuff and 5 more. Nature, 2015

1,767 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/34b5ca35fc48e6213a7b272d44f1e186feae10ff

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Tuo Li
2. S. Tait
3. Zhijian J. Chen
4. Joel S. Riley
5. A. Ablasser
6. G. Shadel
7. W. Zong
8. E. White

In Molecular Biology

1. S. Tait
2. Zhijian J. Chen
3. M. Lazarou
4. A. Ablasser
5. Tuo Li
6. B. Padman
7. Joel S. Riley
8. R. Youle

Citations in the corpus

• Role of neuroinflammation in neurodegeneration development (2023, background): “Besides the exogenous dsDNA released by virus or bacterial, intrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can also bind to cGAS and activate cGASSTING pathway.(400,401) Binding with long dsDNA has been shown to induce the rearran”
• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “Likewise, persistent mitochondrial stress triggers cGAS-dependent cellular responses (69).”
• The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “Haplodeficiency of TFAM (transcription factor A, mitochondria), a protein that packages mitochondria DNA (mtDNA) into nucleoid, was reported to promote releases of mtDNA into the cytosol, which activate cGAS to confer IFN-mediated viral resistance (West et al., 2015).”
• TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, methodology): “Cytosolic DNA immunoprecipitation and subcellular fractionation Following induction of TDP-43 for the time indicated, cell lysates were prepared similarly to a previously published protocol (West et al., 2015).”
• Mitochondrial DNA in inflammation and immunity (2020, positive): “Three independent studies were the first to show that mtDNA released from mitochondria is able to activate cGAS-STING signalling [37 – 39].”
• BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis (2018, background): “Cytosolic mtDNA fragments are also found in cells experiencing mitochondrial stress (10) or inflammasome activation (11); however, the mechanism of mtDNA release in these settings is not clear.”
• Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance (2021, background): “Moreover, TFAM deficiency was shown to induce aberrant packaging of nucleoids, thereby promoting leakage of mtDNA into the cytosol and the production of cytokines [58].”
• Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “143 Such activation is instrumental in engendering a comprehensive antiviral defense mechanism via enhanced expression of a subset of interferon-stimulated genes (ISG).”