Viral infection activates the IRF1-BAK axis to drive mitochondria-derived inflammation.

Mitochondria can drive the development of inflammatory pathogenesis through releasing pro-inflammatory DAMPs, a process often triggered during virus infection. Whether a common mechanism exists that promotes virus-triggered mitochondria-derived inflammation is currently unknown. Here, we report that BAK is an interferon-stimulated gene that is up-regulated by the STAT1-IRF1 axis during virus infection to induce mitochondria-derived inflammatory pathogenesis. Viral infection triggers STAT1-dependent up-regulation of IRF1, which binds to an identified ISRE site in the BAK-promoter, inducing BAK up-regulation. Up-regulated BAK accumulates in the mitochondria triggering mitochondrial outer-membrane permeabilization and inflammatory responses. Both RNA and DNA viruses trigger the IRF1-mediated BAK up-regulation and mitochondria-derived inflammation. Using the Bak-/- mouse model, we showed that both IAV and SFTSV, two viruses that induce severe inflammation in patients, trigger BAK up-regulation and BAK-dependent lethal inflammation. These results reveal a common mechanism that drives mitochondria-derived pathogenic inflammation, which can be targeted for developing anti-inflammatory therapeutics.