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Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation

ABSTRACT: Hypoxia is a hallmark of the tumour microenvironment, driving metabolic reprogramming, immune activation, and genome instability. Here, we showed that cobalt chloride (CoCl2), a hypoxia-mimetic agent, potently induces the expression of the DNA cytidine deaminase APOBEC3A (A3A) in human THP-1 monocytic cells. A3A upregulation occurred in a dose-dependent manner, independently of type I interferon signalling, and was accompanied by increased double-strand DNA breaks. Transcriptomic profiling revealed broad hypoxia-driven reprogramming, characterized by activation of the stress response and downregulation of mitochondrial signalling pathways. Mechanistically, cobalt chloride induced mitochondrial dysfunction, metabolic reprogramming, and cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA was transcribed by RNA polymerase III into immunostimulatory RNA, which activated the RIG-I/TRAF6/NF-κB axis to drive A3A expression. Inhibition or knockdown of RNA polymerase III markedly reduced both A3A levels and DNA damage, highlighting the central role of this pathway. All together, our findings reveal a novel interferon-independent signalling route through which hypoxia-induced mitochondrial stress activates A3A, directly linking metabolic dysfunction to genome instability. This mechanism implicates mitochondrial perturbation as a key driver of APOBEC3-mediated mutagenesis in hypoxic tumours and other diseases associated with mitochondrial stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312974 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. 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 signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation

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