Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity

Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection of macrophages. Here, we implicate the non-canonical TRIM family member TRIM14 in regulating mitochondrial health during Mtb infection. Specifically, we show that TRIM14 constrains apoptosis by maintaining a mitochondrial pool of STAT3. TRIM14-dependent mito-STAT3 limits mitochondrial permeability transition pore opening, thereby preserving mitochondrial integrity and raising the threshold for apoptotic commitment. In the absence of TRIM14, increased STAT3 Ser754 phosphorylation reduces mitochondrial STAT3 localization, promoting mPTP opening and apoptosis. In vivo, Trim14 deficiency enhances apoptosis during Mtb infection and is associated with increased CD8+ T cell activation, consistent with apoptotic cell-driven antimycobacterial immunity. Together, these findings define a TRIM14–mito-STAT3 axis that suppresses protective apoptosis during Mtb infection and pinpoint mito-STAT3 as a potential target for host-directed tuberculosis therapies.