Department of Medicine, Division of Pulmonary, Allergy And Critical Care Medicine; Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Bacteria | Bacterial Infections and Mycoses | Biochemical Phenomena, Metabolism, and Nutrition | Cellular and Molecular Physiology | Microbiology
Mycobacterium tuberculosis induces metabolic reprogramming in macrophages like the Warburg effect. This enhances antimicrobial performance at the expense of increased inflammation, which may promote a pathogen-permissive host environment. Since the NAD(+)-dependent protein deacetylase Sirtuin 3 (SIRT3) is an important regulator of mitochondrial metabolism and cellular redox homeostasis, we hypothesized that SIRT3 modulation mediates M. tuberculosis-induced metabolic reprogramming. Infection of immortalized and primary murine macrophages resulted in reduced levels of SIRT3 mRNA and protein and perturbation of SIRT3-regulated enzymes in the tricarboxylic acid cycle, electron transport chain, and glycolytic pathway. These changes were associated with increased reactive oxygen species and reduced antioxidant scavenging, thereby triggering mitochondrial stress and macrophage cell death. Relevance to tuberculosis disease in vivo was indicated by greater bacterial burden and immune pathology in M. tuberculosis-infected Sirt3 (-/-) mice. CD11b(+) lung leukocytes isolated from infected Sirt3(-/-) mice showed decreased levels of enzymes involved in central mitochondrial metabolic pathways, along with increased reactive oxygen species. Bacterial burden was also greater in lungs of LysM(cre)Sirt3(L2/L2) mice, demonstrating the importance of macrophage-specific SIRT3 after infection. These results support the model of SIRT3 as a major upstream regulatory factor, leading to metabolic reprogramming in macrophages by M. tuberculosis
IMPORTANCE Tuberculosis, the disease caused by the bacterium M. tuberculosis, remains one of the top 10 causes of death worldwide. Macrophages, the first cells to encounter M. tuberculosis and critical for defense against infection, are hijacked by M. tuberculosis as a protected growth niche. M. tuberculosis-infected macrophages undergo metabolic reprogramming where key mitochondrial pathways are modulated, but the mechanisms driving this metabolic shift is unknown. Our study demonstrates that M. tuberculosis downregulates Sirtuin 3 (SIRT3), an important regulator of mitochondrial metabolism, leading to SIRT3-dependent transcriptional downregulation of mitochondrial metabolic proteins, which is followed by oxidative stress and macrophage necrosis. This study identifies SIRT3 modulation as a key event in M. tuberculosis-induced metabolic reprograming in macrophages that defend against tuberculosis.
Mycobacterium tuberculosis, cell death, macrophages, mitochondrial metabolism, sirtuin
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Copyright © 2021 Smulan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
DOI of Published Version
Smulan LJ, Martinez N, Kiritsy MC, Kativhu C, Cavallo K, Sassetti CM, Singhal A, Remold HG, Kornfeld H. Sirtuin 3 Downregulation in Mycobacterium tuberculosis-Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death. mBio. 2021 Feb 2;12(1):e03140-20. doi: 10.1128/mBio.03140-20. PMID: 33531400; PMCID: PMC7858060. Link to article on publisher's site
Smulan LJ, Martinez NM, Kiritsy MC, Kativhu CL, Cavallo K, Sassetti CM, Singhal A, Remold HG, Kornfeld H. (2021). Sirtuin 3 Downregulation in Mycobacterium tuberculosis-Infected Macrophages Reprograms Mitochondrial Metabolism and Promotes Cell Death. Open Access Publications by UMMS Authors. https://doi.org/10.1128/mBio.03140-20. Retrieved from https://escholarship.umassmed.edu/oapubs/4613
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