Mycobacterium tuberculosis Rv0927c promote Type I interferon responses by targeting host TUFM to trigger mitochondrial damage and increase intracellular survival

Mycobacterium tuberculosis (M. tuberculosis) deploys effector proteins to reprogram host immunity, but how it perturbs mitochondrial homeostasis during infection remains incompletely understood. Here, Rv0927c is identified as an M. tuberculosis effector that targets the host mitochondrial translation elongation factor TUFM. Rv0927c associates with TUFM and induces mitochondrial dysfunction, including membrane depolarization, oxidative stress, and PINK1 accumulation, followed by leakage of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA is accompanied by activation of STING-IRF3 signaling and increased production of IFN-β, which promotes intracellular mycobacterial survival. In infection models, genetic deletion of Rv0927c attenuates interferon induction, whereas Rv0927c expression enhances type I interferon responses. Consistently, in a mouse tail vein infection model using H37Ra, Rv0927c is associated with elevated IFN-β transcripts in spleen and liver and exacerbated tissue pathology. Together, these findings define an Rv0927c–TUFM axis that triggers mitochondrial stress and PINK1 accumulation. This response activates STING dependent type I interferon signaling and promotes disease associated inflammation.