M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments

The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation to maintain membrane potential and ATP synthesis. Counterintuitively, we find here that oxygen its...

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Main Authors: Kalia, Nitin Pal, Singh, Samsher, Hards, Kiel, Cheung, Chen-Yi, Sviriaeva, Ekaterina, Banaei-Esfahani, Amir, Aebersold, Ruedi, Berney, Michael, Cook, Gregory M., Pethe, Kevin
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2023
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Online Access:https://hdl.handle.net/10356/169272
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1692722023-07-13T15:30:23Z M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments Kalia, Nitin Pal Singh, Samsher Hards, Kiel Cheung, Chen-Yi Sviriaeva, Ekaterina Banaei-Esfahani, Amir Aebersold, Ruedi Berney, Michael Cook, Gregory M. Pethe, Kevin Lee Kong Chian School of Medicine (LKCMedicine) Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) Science::Medicine Science::Biological sciences Bioenergetics Granuloma The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation to maintain membrane potential and ATP synthesis. Counterintuitively, we find here that oxygen itself is the principal terminal electron acceptor during hypoxic dormancy. M. tuberculosis can metabolize oxygen efficiently at least two orders of magnitude below the concentration predicted to occur in hypoxic lung granulomas. Despite a difference in apparent affinity for oxygen, both the cytochrome bcc:aa3 and cytochrome bd oxidase respiratory branches are required for hypoxic respiration. Simultaneous inhibition of both oxidases blocks oxygen consumption, reduces ATP levels, and kills M. tuberculosis under hypoxia. The capacity of mycobacteria to scavenge trace levels of oxygen, coupled with the absence of complex regulatory mechanisms to achieve hierarchal control of the terminal oxidases, may be a key determinant of long-term M. tuberculosis survival in hypoxic lung granulomas. National Research Foundation (NRF) Published version This work was supported by the National Research Foundation (NRF) Singapore under its Investigatorship Program (grant NRF-NRFI06-2020-0004) and the NRF Competitive Research Program (project award numbers NRF-CRP18–2017–01 and NRF-CRP27-2021-0002, to K.P.) and by the National Institutes of Health USA (R01 AI139465, to M.B.). K.H. and G.M.C. were funded by Marsden grants awarded by the Royal Society of New Zealand and a Health Research Council of New Zealand grant. 2023-07-11T01:10:50Z 2023-07-11T01:10:50Z 2023 Journal Article Kalia, N. P., Singh, S., Hards, K., Cheung, C., Sviriaeva, E., Banaei-Esfahani, A., Aebersold, R., Berney, M., Cook, G. M. & Pethe, K. (2023). M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments. Cell Reports, 42(5), 112444-. https://dx.doi.org/10.1016/j.celrep.2023.112444 2211-1247 https://hdl.handle.net/10356/169272 10.1016/j.celrep.2023.112444 37115669 2-s2.0-85153485648 5 42 112444 en NRF-NRFI06-2020-0004 NRF-CRP18-2017-01 NRF-CRP27-2021-0002 Cell Reports © 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Science::Biological sciences
Bioenergetics
Granuloma
spellingShingle Science::Medicine
Science::Biological sciences
Bioenergetics
Granuloma
Kalia, Nitin Pal
Singh, Samsher
Hards, Kiel
Cheung, Chen-Yi
Sviriaeva, Ekaterina
Banaei-Esfahani, Amir
Aebersold, Ruedi
Berney, Michael
Cook, Gregory M.
Pethe, Kevin
M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
description The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation to maintain membrane potential and ATP synthesis. Counterintuitively, we find here that oxygen itself is the principal terminal electron acceptor during hypoxic dormancy. M. tuberculosis can metabolize oxygen efficiently at least two orders of magnitude below the concentration predicted to occur in hypoxic lung granulomas. Despite a difference in apparent affinity for oxygen, both the cytochrome bcc:aa3 and cytochrome bd oxidase respiratory branches are required for hypoxic respiration. Simultaneous inhibition of both oxidases blocks oxygen consumption, reduces ATP levels, and kills M. tuberculosis under hypoxia. The capacity of mycobacteria to scavenge trace levels of oxygen, coupled with the absence of complex regulatory mechanisms to achieve hierarchal control of the terminal oxidases, may be a key determinant of long-term M. tuberculosis survival in hypoxic lung granulomas.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Kalia, Nitin Pal
Singh, Samsher
Hards, Kiel
Cheung, Chen-Yi
Sviriaeva, Ekaterina
Banaei-Esfahani, Amir
Aebersold, Ruedi
Berney, Michael
Cook, Gregory M.
Pethe, Kevin
format Article
author Kalia, Nitin Pal
Singh, Samsher
Hards, Kiel
Cheung, Chen-Yi
Sviriaeva, Ekaterina
Banaei-Esfahani, Amir
Aebersold, Ruedi
Berney, Michael
Cook, Gregory M.
Pethe, Kevin
author_sort Kalia, Nitin Pal
title M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
title_short M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
title_full M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
title_fullStr M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
title_full_unstemmed M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
title_sort m. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
publishDate 2023
url https://hdl.handle.net/10356/169272
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