M. tuberculosis relies on trace oxygen to maintain energy homeostasis and survive in hypoxic environments
Nitin Pal Kalia,
Samsher Singh,
Kiel Hards,
Chen-Yi Cheung,
Ekaterina Sviriaeva,
Amir Banaei-Esfahani,
Ruedi Aebersold,
Michael Berney,
Gregory M. Cook,
Kevin Pethe
Affiliations
Nitin Pal Kalia
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore; Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER-H) Hyderabad, Hyderabad, Telangana 500037, India
Samsher Singh
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
Kiel Hards
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 92019, New Zealand
Chen-Yi Cheung
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
Ekaterina Sviriaeva
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
Amir Banaei-Esfahani
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8057 Zurich, Switzerland
Ruedi Aebersold
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8057 Zurich, Switzerland; Faculty of Science, University of Zurich, 8057 Zurich, Switzerland
Michael Berney
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Gregory M. Cook
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 92019, New Zealand; Corresponding author
Kevin Pethe
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore; National Centre for Infectious Diseases, Singapore 308442, Singapore; Corresponding author
Summary: 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.