Targeting macrophage mitochondrial metabolism in tuberculosis: from pathogen-driven biochemical reprogramming to host-directed pharmacotherapy.

Mycobacterium tuberculosis (Mtb) remains a leading global health threat. The fate of the Mtb-infected macrophage is critically governed by host mitochondrial metabolism. In this review, we propose a unifying biochemical "threshold model" of tuberculosis pathogenesis: Mtb functions as an intracellular "mitochondrial parasite," deploying multiple effectors-including ESAT-6, PtpA, and TNT-that perturb host mitochondrial or mitochondria-linked metabolic pathways, spanning oxidative phosphorylation, NAD+ homeostasis, TCA cycle remodeling, and ATP synthesis. This cumulative biochemical damage is predicted to progressively lower the macrophage threshold for TNF-induced programmed necrosis, a cell death modality executed through reverse electron transport (RET) and reactive oxygen species (ROS) generation at mitochondrial complex I. This metabolic-necrotic axis may therefore present druggable vulnerabilities. We evaluate emerging small-molecule host-directed therapies (HDTs) that counter these pathogenic mechanisms by targeting specific mitochondrial nodes, including succinate dehydrogenase (SDH), mitochondrial complex I, pyruvate dehydrogenase kinase (PDK), SIRT3, and the ACOD1/itaconate axis. For each pharmacological class, we discuss its biochemical mechanism of action and translational potential. Our threshold model predicts that restoring selected mitochondrial functions may reduce macrophage susceptibility to lytic death and bacterial dissemination; whether individual interventions actively redirect infected macrophages toward apoptosis, rather than simply preserving cell viability, requires direct experimental testing.