NIX-mediated mitophagy regulate metabolic reprogramming in phagocytic cells during mycobacterial infection

RNASeq analysis of PBMCs from treatment naive TB patients and healthy controls revealed that M. tuberculosis (Mtb) infection dysregulates several metabolic pathways and upregulates BNIP3L/NIX receptor mediated mitophagy. Analysis of publicly available transcriptomic data from the NCBI-GEO database indicated that M. bovis (BCG) infection also induces similar rewiring of metabolic and mitophagy pathways. Mtb chronic infection and BCG in-vitro infection both downregulated oxidative phosphorylation and upregulated glycolysis and mitophagy; therefore, we used non-pathogenic mycobacterial species BCG as a model for Mtb infection to gain molecular insights and outcomes of this phenomenon. BCG infection in PBMCs and THP-1 macrophages induce mitophagy and glycolysis, leading to differentiation of naive macrophage to M1 phenotype. Glucose consumption and lactate production were quantified by NMR, while the mitochondrial mass assessment was performed by mitotracker red uptake assay. Infected macrophages predominantly exhibit Ml-phenotype, which is indicated by an increase in M1 specific cytokines (IL-6, TNF-alpha, and IL-1 beta) and increased NOS2/ARG1, CD86/CD206 ratio. NIX knockdown abrogates this upregulation of glycolysis, mitophagy, and secretion of proinflammatory cytokines in BCG infected cells, indicating that mycobacterial infection-induced immunometabolic changes are executed via NIX mediated mitophagy and are essential for macrophage differentiation and resolution of infection.

Automated summary

Analysis of RNASeq data from PBMCs of treatment naive TB patients and healthy controls showed dysregulation of metabolic pathways and upregulation of mitophagy due to M. tuberculosis (Mtb) infection. Transcriptomic data from NCBI-GEO database indicated that M. bovis (BCG) infection also induces similar metabolic rewiring and mitophagy pathways. Chronic Mtb infection and BCG in-vitro infection downregulated oxidative phosphorylation while upregulating glycolysis and mitophagy, suggesting non-pathogenic mycobacterial species BCG can be used as a model for studying Mtb infection outcomes.