Intracellular Mycobacterium tuberculosis Exploits Host-derived Fatty Acids to Limit Metabolic Stress
Open accessAbstract
Recent data indicate that the nutrients available to Mycobacterium tuberculosis (Mtb) inside its host cell are restricted in their diversity. Fatty acids and cholesterol appear more favored; however, their degradation can result in certain metabolic stresses. Their breakdown can generate propionyl-CoA, which gives rise to potentially toxic intermediates. Detoxification of propionyl-CoA relies on the activity of the methylcitrate cycle, the methylmalonyl pathway, or incorporation of the propionyl-CoA into methyl-branched lipids in the cell wall. The current work explores carbon flux through these pathways, focusing primarily on those pathways responsible for the incorporation of propionyl-CoA into virulence-associated cell wall lipids. Exploiting both genetic and biochemical rescue, we demonstrate that these metabolic pressures are experienced by Mtb inside its host macrophage and that the bacterium accesses host fatty acid stores. The metabolism of these host lipids expands the acetyl-CoA pool and alleviates the pressure from propionyl-CoA. These data have major implications for our appreciation of central metabolism of Mtb during the course of infection. Background: The metabolism of host lipids is central to the survival of intracellular Mtb. Results: Degradation of cholesterol generates propionyl-CoA, which is, in part, detoxified through incorporation into methyl-branched lipids. Conclusion: The balance of acetyl-CoA versus propionyl-CoA concentrations in Mtb impacts detoxification of propionyl-CoA. Significance: The ability of Mtb to utilize host-derived lipids effectively is key to its success as a pathogen.
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Breakdown products of fatty acids, such as propionyl-coenzyme A, can exert toxic effects toward mycobacteria, which detoxify this intermediate by converting it to acetyl-CoA for use as a central metabolic compound.
“Of interest, breakdown products of fatty acids, such as propionyl–coenzyme A, can exert toxic effects toward mycobacteria, which thus try to detoxify this intermediate by converting it to acetyl-CoA that can be then used by bacteria as a central metabolic compound (91).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [91]
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- Authors
- Lee, W., VanderVen, B. C., Fahey, R. J., & Russell, D. G.
- Affiliations
- Cornell University (US)
- Corresponding author
- Russell, David G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 288
- Issue
- 10
- Pages
- 6788-6800
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3591590
- OpenAlex
- W2022093637
- Cited by
- 424
- References
- 49
- Citations by year
- 2026: 27 · 2025: 36 · 2024: 33 · 2023: 31 · 2022: 27 · 2021: 36 · 2020: 25 · 2019: 39 · 2018: 36 · 2017: 34 · 2016: 35 · 2015: 22 · 2014: 26 · 2013: 14
- FWCI
- 23.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 055936, R01HL055936)
- National Institute of Allergy and Infectious Diseases (AI080651, R01AI067027, AI 067027, R01AI080651)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- Mycobacterium tuberculosis, methylcitrate cycle, cholesterol degradation, acetyl-CoA, macrophage infection, metabolic stress
- MeSH terms
- Acetyl Coenzyme A, Acyl Coenzyme A, Animals, Bacterial Proteins, Cells, Cultured, Cholesterol, Fatty Acids, Macrophages, Mice, Inbred C57BL, Models, Biological, Mutation, Mycobacterium tuberculosis, Oxidation-Reduction, Stearic Acids, Stress, Physiological, Gene Expression Regulation, Bacterial, Lipid Metabolism, Mice, Host-Pathogen Interactions
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