NRF1‐mediated mitochondrial biogenesis antagonizes innate antiviral immunity

Abstract Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor‐1 (NRF1), a vital transcriptional factor involved in nuclear‐mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV‐1) virus‐induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1‐mediated mitochondrial biogenesis aggravated virus‐induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus‐activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1‐TFAM axis during HSV‐1 infection. A knock‐in (KI) strategy that mimicked TBK1‐NRF1 signaling revealed that interrupting the TBK1‐NRF1 connection ablated mtDNA release and thereby attenuated the HSV‐1‐induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1‐mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response.