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Perturbation of cytochrome c maturation reveals adaptability of the respiratory chain in Mycobacterium tuberculosis.

TitlePerturbation of cytochrome c maturation reveals adaptability of the respiratory chain in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsSmall JL, Park SWoong, Kana BD, Ioerger TR, Sacchettini JC, Ehrt S
JournalmBio
Volume4
Issue5
Paginatione00475-13
Date Published2013 Sep 17
ISSN2150-7511
KeywordsAnimals, Bacterial Proteins, Cytochromes c, Electron Transport, Electron Transport Complex IV, Female, Heme, Humans, Male, Mice, Inbred C57BL, Mycobacterium tuberculosis, Oxygen, Thioredoxins, Tuberculosis
Abstract

UNLABELLED: Mycobacterium tuberculosis depends on aerobic respiration for growth and utilizes an aa3-type cytochrome c oxidase for terminal electron transfer. Cytochrome c maturation in bacteria requires covalent attachment of heme to apocytochrome c, which occurs outside the cytoplasmic membrane. We demonstrate that in M. tuberculosis the thioredoxin-like protein Rv3673c, which we named CcsX, is required for heme insertion in cytochrome c. Inactivation of CcsX resulted in loss of c-type heme absorbance, impaired growth and virulence of M. tuberculosis, and induced cytochrome bd oxidase. This suggests that the bioenergetically less efficient bd oxidase can compensate for deficient cytochrome c oxidase activity, highlighting the flexibility of the M. tuberculosis respiratory chain. A spontaneous mutation in the active site of vitamin K epoxide reductase (VKOR) suppressed phenotypes of the CcsX mutant and abrogated the activity of the disulfide bond-dependent alkaline phosphatase, which shows that VKOR is the major disulfide bond catalyzing protein in the periplasm of M. tuberculosis.

IMPORTANCE: Mycobacterium tuberculosis requires oxygen for growth; however, the biogenesis of respiratory chain components in mycobacteria has not been explored. Here, we identified a periplasmic thioredoxin, CcsX, necessary for heme insertion into cytochrome c. We investigated the consequences of disrupting cytochrome c maturation (CCM) for growth and survival of M. tuberculosis in vitro and for its pathogenesis. Appearance of a second-site suppressor mutation in the periplasmic disulfide bond catalyzing protein VKOR indicates the strong selective pressure for a functional cytochrome c oxidase. The observation that M. tuberculosis is able to partially compensate for defective CCM by upregulation of the cytochrome bd oxidase exposes a functional role of this alternative terminal oxidase under normal aerobic conditions and during pathogenesis. This suggests that targeting both oxidases simultaneously might be required to effectively disrupt respiration in M. tuberculosis.

DOI10.1128/mBio.00475-13
Alternate JournalmBio
PubMed ID24045640
PubMed Central IDPMC3781833
Grant ListR01 AI081725 / AI / NIAID NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
AI081725 / AI / NIAID NIH HHS / United States
T32GM07739 / GM / NIGMS NIH HHS / United States

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