NIX-mediated mitophagy regulate metabolic reprogramming in phagocytic cells during mycobacterial infection
Open accessAbstract
RNASeq analysis of PBMCs from treatment naïve 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 naïve 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 M1-phenotype, which is indicated by an increase in M1 specific cytokines (IL-6, TNF-α, and IL-1β) and increased NOS2/ARG1, CD86/CD206 ratio. NIX knockdown abrogates this upregulation of glycolysis, mitophagy, and secretion of pro-inflammatory 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.
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Macrophages are the first immune cells to encounter invading pathogens and engulf microbes, dead cells, foreign substances, cancer cells and cellular debris by phagocytosis.
“Macrophages (from Greek: large eaters, makros + phagein), are the first immune cells to encounter invading pathogens, and their goal is to engulf microbes, dead cells, foreign substances, cancer cells and cellular debris by phagocytosis [183].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [183]
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- Authors
- Mahla, R. S., Kumar, A., Tutill, H. J., Krishnaji, S. T., Sathyamoorthy, B., Noursadeghi, M., Breuer, J., Pandey, A. K., & Kumar, H.
- Affiliations
- Indian Institute of Science Education and Research, Bhopal (IN)
- University College London (GB)
- Great Ormond Street Hospital (GB)
- Translational Health Science and Technology Institute (IN)
- Corresponding author
- Kumar, Akhilesh
- Kumar, Himanshu
- ORCID
- Venue
- Tuberculosis
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 126
- Pages
- 102046
- ISSN
- 1472-9792 (ISSN-L)
- PMC
- PMC7619460
- OpenAlex
- W3117307511
- Cited by
- 28
- References
- 41
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 2
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Licence
- Locations
- Tuberculosis (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- British Council
- Indian Institute of Science Education and Research Bhopal
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Nix, mitophagy, metabolic reprogramming, Mycobacterium tuberculosis infection, Mycobacterium bovis BCG, phagocytes, macrophage polarization, glycolysis, oxidative phosphorylation, immunometabolism, inflammatory cytokines
- MeSH terms
- Cell Differentiation, Cells, Cultured, DNA, Gene Expression Regulation, Humans, Macrophages, Membrane Proteins, Mycobacterium tuberculosis, Proto-Oncogene Proteins, Tuberculosis, Apoptosis, Tumor Suppressor Proteins, Mitophagy
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