Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT 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 d...

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Autores principales:	Jennifer L. Small, Sae Woong Park, Bavesh D. Kana, Thomas R. Ioerger, James C. Sacchettini, Sabine Ehrt
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/07e11785900e4ca0bdf5870ec4ebc63f
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spelling	oai:doaj.org-article:07e11785900e4ca0bdf5870ec4ebc63f2021-11-15T15:42:47ZPerturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mBio.00475-132150-7511https://doaj.org/article/07e11785900e4ca0bdf5870ec4ebc63f2013-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00475-13https://doaj.org/toc/2150-7511ABSTRACT 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.Jennifer L. SmallSae Woong ParkBavesh D. KanaThomas R. IoergerJames C. SacchettiniSabine EhrtAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 5 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Jennifer L. Small Sae Woong Park Bavesh D. Kana Thomas R. Ioerger James C. Sacchettini Sabine Ehrt Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT 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.
format	article
author	Jennifer L. Small Sae Woong Park Bavesh D. Kana Thomas R. Ioerger James C. Sacchettini Sabine Ehrt
author_facet	Jennifer L. Small Sae Woong Park Bavesh D. Kana Thomas R. Ioerger James C. Sacchettini Sabine Ehrt
author_sort	Jennifer L. Small
title	Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	perturbation of cytochrome <italic toggle="yes">c</italic> maturation reveals adaptability of the respiratory chain in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/07e11785900e4ca0bdf5870ec4ebc63f
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Perturbation of Cytochrome <italic toggle="yes">c</italic> Maturation Reveals Adaptability of the Respiratory Chain in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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