Mitochondrial DNA stress primes the antiviral innate immune response

A. Phillip West, William Khoury-Hanold, Matthew Staron, Michal C. Tal, Cristiana M. Pineda, Sabine M. Lang, Megan Bestwick, Brett A. Duguay, Nuno Raimundo, Donna A. MacDuff, Susan M. Kaech, James R. Smiley, Robert E. Means, Akiko Iwasaki, Gerald S. Shadel

Research output: Contribution to journalArticlepeer-review

557 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)553-557
Number of pages5
JournalNature
Volume520
Issue number7548
DOIs
StatePublished - Apr 23 2015

All Science Journal Classification (ASJC) codes

  • General

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