A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused byMycobacterium tuberculosis

Abstract

AbstractPhagosome maturation arrest (PMA) imposed byMycobacterium tuberculosis(Mtb) is a classic tool that helpsMtbevade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, fromMtb-phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion (p62KD) blocks mitophagy flux without impacting mitochondrial quality. Inp62KDcells,Mtbgrowth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting ofMtbis facilitated by enhanced TOM20+mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. Inp62KDcells, TOM20+-MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection inp62KDcells, TOM20+-MDVs get extensively targeted toMtb-phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting ofMtb. Triggering MQC collapse inp62KDcells further diminishesMtbsurvival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.