Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria

Abstract

Mycobacteria inhabit a wide range of intracellular and extracellular environments. Many of these environments are highly dynamic and therefore mycobacteria are faced with the constant challenge of redirecting their metabolic activity to be commensurate with either replicative growth or a non-replicative quiescence. A fundamental feature in this adaptation is the ability of mycobacteria to respire, regenerate reducing equivalents and generate ATP via oxidative phosphorylation. Mycobacteria harbor multiple primary dehydrogenases to fuel the electron transport chain and two terminal respiratory oxidases, an aa3 -type cytochrome c oxidase and cytochrome bd-type menaquinol oxidase, are present for dioxygen reduction coupled to the generation of a protonmotive force. Hypoxia leads to the downregulation of key respiratory complexes, but the molecular mechanisms regulating this expression are unknown. Despite being obligate aerobes, mycobacteria have the ability to metabolize in the absence of oxygen and a number of reductases are present to facilitate the turnover of reducing equivalents under these conditions (e.g. nitrate reductase, succinate dehydrogenase/fumarate reductase). Hydrogenases and ferredoxins are also present in the genomes of mycobacteria suggesting the ability of these bacteria to adapt to an anaerobic-type of metabolism in the absence of oxygen. ATP synthesis by the membrane-bound F1FO-ATP synthase is essential for growing and non-growing mycobacteria and the enzyme is able to function over a wide range of protonmotive force values (aerobic to hypoxic). The discovery of lead compounds that target respiration and oxidative phosphorylation in Mycobacterium tuberculosis highlights the importance of this area for the generation of new front line drugs to combat tuberculosis.

Figure 1

Organization and components of the electron transport chain in mycobacteria.

Figure 2

The core respiratory chain of Mycobacteria and components upregulated under energy-limiting conditions. During in vitro exponential growth, Mycobacteria use a classical respiratory chain composed of a Type I NADH:Menaquinone oxidoreductase (Nuo), Succinate:Menaquinone oxidoreductase 1 (SDH1), Cytochrome aa₃-bc supercomplex (Qcr-Cta) and F₁F_o ATPase. Menaquinone (MQ) is the only quinone present in mycobacterial membranes and reverse electron transport driven by the proton motive force is proposed to facilitate the function of SDH1 and similar enzymes (see text). Components coloured in light blue are upregulated in response to energy-limiting conditions (6). Catalysis and electron flow are indicated by arrows. Other acronyms: Cox – Carbon monoxide dehydrogenase; Hyd – Hydrogenase; DH – Dehydrogenase; A – Unidentified electron acceptor.

Figure 3

The preferential respiratory chain of an oxygen-limited mycobacterial cell. Under low oxygen-conditions a diverse response utilizing alternate electron donors and acceptors, energy-conserving enzymes and a high affinity terminal oxidase permit survival under hypoxic conditions. Components coloured in red are upregulated under microaerobic conditions (6). Catalysis and electron flow are indicated by arrows. The possible PMF-driven reverse electron flow of Sdh2 is not shown for clarity. Acronyms: Mqo – Malate:Menaquinone oxidoreductase; Ndh – Type II NADH:Menaquinone oxidoreductase; Sdh2 – Succinate:Menaquinone oxidoreductase 2; Nar – Nitrate reductase; Cyd – Cytochrome bd oxidase; Frd – Fumarate reductase; Hyd – Hydrogenase; MQ – Menaquinone; A – Unidentified electron acceptor.