A unique Mitochondrial Quality Control (MQC) mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis

Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis (Mtb) is among the classic tools that helps Mtb evade macrophage anti-bacterial response. Here we report a unique crosstalk between mitochondrial quality control (MQC) pathways and the phagosome maturation pathway, which unblocks the PMA and results in the efficient killing of Mtb. Depletion of p62/SQSTM1, a major autophagy adaptor, in human macrophages enhances Mtb killing. However, depletion of p62/SQSTM1 does not impact mitochondrial quality, despite an apparent block in mitophagy flux. Interestingly, in p62KD cells, MQC is ensured via TOM20+-mitochondria-derived vesicles (MDVs). MDVs, being dependent on RAB7 for maturation, are heavily recruited on Mtb-phagosomes in p62KD cells inadvertently aiding RAB7 recruitment on Mtb-phagosomes thereby releasing the PMA that facilitates efficient lysosomal delivery and killing of Mtb. Finally, blocking MQC in the p62KD cells, augments bacterial killing, underscoring the crosstalk between MQC and host-antibacterial mechanisms, providing an unexplored host-directed therapy strategy against tuberculosis.