Mitochondrial DNA stress primes the antiviral innate immune response, 2015, Shadel et al

Andy · Mar 11, 2019

Abstract
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids1. The abundant mtDNA-binding protein, transcription factor A mitochondrial (TFAM), regulates nucleoid architecture, abundance, and segregation2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation (OXPHOS), triggering calcium-dependent stress signaling and adaptive metabolic responses3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and aging, remain ill-defined4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signaling to enhance the expression
of a subset of interferon-stimulated genes (ISG).

Mechanistically, we have found that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS and promotes STING-IRF3-dependent signaling to elevate ISG expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which potentiates antiviral signaling 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 signaling, and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully license antiviral innate immunity.
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Open access at http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4409480&blobtype=pdf

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Mitochondrial DNA stress primes the antiviral innate immune response, 2015, Shadel et al

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Mitochondrial DNA stress primes the antiviral innate immune response, 2015, Shadel et al

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