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. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo, loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8+ T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity.