Defense and subversion: multilevel mitochondrial quality control and pathway‑specific mitophagy outcomes in Mycobacterium tuberculosis infection

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of infectious mortality worldwide, a burden compounded by rising drug resistance. While mitochondria were long dismissed as mere powerhouses, they now function as hubs that integrate immune metabolism, innate immune signaling, and cell-death decisions. During infection, M.tb severely disrupts these hubs through organelle swelling, cristae remodeling, mitochondrial DNA release, and rewired oxidative phosphorylation. Despite this disruption, the field remains divided over whether mitophagy, the terminal tier of quality control, protects the host or serves the pathogen. The answer depends on the pathway engaged. Here, we synthesize evidence that M.tb engages a multilevel mitochondrial quality control network spanning chaperones and proteases, the integrated stress response, fusion and fission dynamics, and mitophagy. We propose that distinct mitophagy pathways yield mechanistically distinct, context-dependent outcomes during mycobacterial infection. Notably, the PINK1 and Parkin axis mediates both protective antibacterial xenophagy and pathogen-exploited mitophagy. Beyond this axis, BNIP3, NIX, and FUNDC1 can limit or promote bacterial survival, depending on pathway identity, infection stage, and host-cell metabolic state. This framework offers a way to interpret effects that appear to conflict, whether they protect the host or favor the pathogen, traces the outcome to which pathway is engaged, the context of infection, and the state of the host cell, and identifies specific MQC nodes, including mitochondrial reactive oxygen species thresholds and the PINK1-Parkin axis, as candidate targets for host-directed therapy.