Abstract

Mycobacterium tuberculosis (Mtb) is an intracellular parasitic pathogen that infects humans and potentially causes tuberculosis. In addition, emerging evidence suggests that Mtb infection can elicit distinct immune responses in different subcellular organelles; however, the underlying molecular mechanisms remain poorly understood. In this study, we determined that Mtb infection can suppress the expression of mitochondrial-localized fatty acid-binding protein 4 (FABP4), promote lipid peroxidation, and induce ferroptosis, thereby facilitating the intracellular proliferation and dissemination of the pathogen. Upon overexpressing mitochondrial FABP4, we discovered that the downregulation of PPARG coactivator 1 alpha (PGC-1α) and uncoupling protein 2 (UCP2) induced by Mtb infection were inhibited, resulting in lower mitochondrial superoxide levels, reduced reactive oxygen species levels, and suppressed lipid peroxidation. In addition, FABP4 overexpression in mitochondria resulted in normalization of the expression of ferroptosis marker glutathione peroxidase 4, thereby suppressing the proliferation of Mtb and the resulting cellular damage. In summary, our findings provide new insights into the molecular mechanisms of tuberculosis pathogenicity, suggesting that studying the immune responses elicited by pathogen infection in different organelles holds significant potential for guiding future research. Graphical By establishing an organelle-resolved model of macrophages infected with Mycobacterium tuberculosis, we identified a larger and more functionally informative set of differentially expressed genes than is attainable with conventional bulk-cell RNA-seq; these genes display distinct organellar localization and biological significance. By integrating transcriptome profiling with mitochondria-targeted rescue expression, we pinpointed FABP4 as the pivotal protein. By localizing to mitochondria, FABP4 preserves mitochondrial functional homeostasis and thereby inhibits My