Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis

• DOI: 10.1073/pnas.1219375110
• Publication Date: 2013-04-01T21:35:20Z
• Authors: Hyungjin Eoh; Kyu Y. Rhee
• Keywords: 0301 basic medicine; Analysis of Variance; Carbon Isotopes; Citric Acid Cycle; Succinic Acid; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Adaptation, Physiological; Isocitrate Lyase; Mass Spectrometry; Membrane Potentials; 3. Good health; Oxygen; 03 medical and health sciences; Adenosine Triphosphate; Metabolomics; Anaerobiosis; Chromatography, Liquid; DNA Primers

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.