Mitochondrial-Localized FABP4 Inhibits Ferroptosis-Dependent Mycobacterium tuberculosis Dissemination by Maintaining Mitochondrial Homeostasis.

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.