Succinate dehydrogenase is the regulator of respiration in Mycobacterium tuberculosis.

Travis Hartman,William R Jacobs,Brian Weinrick,Gregory M Cook,Joanne Tufariello,Catherine Vilchèze,Michael Berney,Marcel A Behr

doi:10.1371/journal.ppat.1004510

Abstract

In chronic infection, Mycobacterium tuberculosis bacilli are thought to enter a metabolic program that provides sufficient energy for maintenance of the protonmotive force, but is insufficient to meet the demands of cellular growth. We sought to understand this metabolic downshift genetically by targeting succinate dehydrogenase, the enzyme which couples the growth processes controlled by the TCA cycle with the energy production resulting from the electron transport chain. M. tuberculosis contains two operons which are predicted to encode succinate dehydrogenase enzymes (sdh-1 and sdh-2); we found that deletion of Sdh1 contributes to an inability to survive long term stationary phase. Stable isotope labeling and mass spectrometry revealed that Sdh1 functions as a succinate dehydrogenase during aerobic growth, and that Sdh2 is dispensable for this catalysis, but partially overlapping activities ensure that the loss of one enzyme can incompletely compensate for loss of the other. Deletion of Sdh1 disturbs the rate of respiration via the mycobacterial electron transport chain, resulting in an increased proportion of reduced electron carrier (menaquinol) which leads to increased oxygen consumption. The loss of respiratory control leads to an inability to recover from stationary phase. We propose a model in which succinate dehydrogenase is a governor of cellular respiration in the adaptation to low oxygen environments.

Highlights

The World Health Organization has estimated the prevalence of Tuberculosis (TB) in the human population to be nearly two billion people
This work establishes the principle that Mycobacterium tuberculosis undergoes a metabolic remodeling as oxygen concentrations fall that serves to decrease its rate of oxygen consumption and oxidative phosphorylation
Among enzymes with a bioenergetic function, genes involved in energy metabolism, and a number of oxidoreductases were found to be important for this transition suggesting that the resumption of growth requires the benefits of oxidative phosphorylation [9]

Summary

Introduction

The World Health Organization has estimated the prevalence of Tuberculosis (TB) in the human population to be nearly two billion people. The organism responsible for this disease, Mycobacterium tuberculosis, owes its unqualified success as a pathogen to the ability to survive and persist in a human host, where it can evade immune surveillance and establish a sub-clinical infection. These latently infecting bacilli have the potential for reactivation in certain circumstances, as is commonly seen in HIV-induced immunosuppression [2]. The current antibiotic therapy regimen recommended by the WHO is multiphasic and is modeled around the presence of tolerant persister cells that are not cleared in the initial two months of treatment. The physiological adaptation which enables this organism to persist remains an area of active research, but targeting persisters should considerably improve the outcome of therapeutic efforts

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