Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation - PubMed
4 hours ago
- #mitochondrial stress
- #APOBEC3A
- #hypoxia
- Hypoxia-mimicking agent cobalt chloride (CoCl₂) induces APOBEC3A (A3A) expression in THP-1 monocytic cells.
- A3A upregulation leads to increased double-strand DNA breaks, independent of type I interferon signaling.
- Hypoxia-driven mitochondrial dysfunction causes metabolic reprogramming and cytosolic release of mitochondrial DNA (mtDNA).
- Cytosolic mtDNA is transcribed by RNA polymerase III into immunostimulatory RNA, activating RIG-I/TRAF6/NF-κB signaling to drive A3A expression.
- Inhibition of RNA polymerase III reduces A3A levels and DNA damage, highlighting its central role.
- The study reveals an interferon-independent pathway linking hypoxia-induced mitochondrial stress to APOBEC3-mediated genome instability in tumors.