Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis
Open accessAbstract
Mycobacterium tuberculosis is a chronic, facultative intracellular pathogen that spends the majority of its decades-long life cycle in a non- or slowly replicating state. However, the bacterium remains poised to resume replicating so that it can transmit itself to a new host. Knowledge of the metabolic adaptations used to facilitate entry into and exit from nonreplicative states remains incomplete. Here, we apply 13 C-based metabolomic profiling to characterize the activity of M. tuberculosis tricarboxylic acid cycle during adaptation to and recovery from hypoxia, a physiologically relevant condition associated with nonreplication. We show that, as M. tuberculosis adapts to hypoxia, it slows and remodels its tricarboxylic acid cycle to increase production of succinate, which is used to flexibly sustain membrane potential, ATP synthesis, and anaplerosis, in response to varying degrees of O 2 limitation and the presence or absence of the alternate electron acceptor nitrate. This remodeling is mediated by the bifunctional enzyme isocitrate lyase acting in a noncanonical role distinct from fatty acid catabolism. Isocitrate lyase-dependent production of succinate affords M. tuberculosis with a unique and bioenergetically efficient metabolic means of entry into and exit from hypoxia-induced quiescence.
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A more recent study suggests the glyoxylate shunt, not the reverse TCA cycle, is used to metabolize glycolytic and fatty acid carbon sources in response to oxygen limitation, producing succinate.
“A more recent study suggests that the glyoxylate shunt, and not the reverse TCA, is used to metabolize both glycolytic and fatty acid carbon sources in response to oxygen limitation and this route also produces succinate as its metabolic end product (43).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [43]
During oxygen limitation, large amounts of succinate are produced by this pathway and used to sustain membrane potential, ATP synthesis, and TCA cycle precursors.
“The authors propose that during oxygen limitation large amounts of succinate are produced by this pathway that are used to sustain the membrane potential, ATP synthesis and TCA cycle precursors akin to a “metabolic battery” (43).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [43]
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“A more recent study suggests that the glyoxylate shunt, and not the reverse TCA, is used tometabolize both glycolytic and fatty acid carbon sources in response to oxygen limitation, and this route also produces succinate as its metabolic end product (43).”
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- Authors
- Eoh, H., & Rhee, K. Y.
- Affiliations
- Weill Cornell Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04
- Volume
- 110
- Issue
- 16
- Pages
- 6554-6559
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3631649
- OpenAlex
- W2109429880
- Cited by
- 278
- References
- 49
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 14 · 2023: 17 · 2022: 17 · 2021: 23 · 2020: 20 · 2019: 25 · 2018: 22 · 2017: 22 · 2016: 20 · 2015: 35 · 2014: 27 · 2013: 5
- FWCI
- 21.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bill and Melinda Gates Foundation
- Hearst Foundations
- Stony Wold-Herbert Fund
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI081094, R21AI081094)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Mycobacterium tuberculosis, succinate metabolism, hypoxia adaptation, isocitrate lyase, quiescence, membrane potential, ATP production, anaplerosis, nitrate as electron acceptor, bacterial metabolism
- MeSH terms
- Adaptation, Physiological, Adenosine Triphosphate, Anaerobiosis, Analysis of Variance, Carbon Isotopes, Chromatography, Liquid, Citric Acid Cycle, Isocitrate Lyase, Membrane Potentials, Mycobacterium tuberculosis, Oxygen, Mass Spectrometry, DNA Primers, Succinic Acid, Metabolomics, Real-Time Polymerase Chain Reaction
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