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Mitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei.

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cam.issuedOnline2018-07-18
dc.contributor.authorDewar, Caroline E
dc.contributor.authorMacGregor, Paula
dc.contributor.authorCooper, Sinclair
dc.contributor.authorGould, Matthew K
dc.contributor.authorMatthews, Keith R
dc.contributor.authorSavill, Nicholas J
dc.contributor.authorSchnaufer, Achim
dc.contributor.orcidDewar, Caroline E [0000-0002-0107-6985]
dc.contributor.orcidMacGregor, Paula [0000-0003-0919-3745]
dc.contributor.orcidCooper, Sinclair [0000-0002-0371-1591]
dc.contributor.orcidSavill, Nicholas J [0000-0002-9769-6168]
dc.contributor.orcidSchnaufer, Achim [0000-0003-2132-5560]
dc.date.accessioned2018-11-22T00:30:39Z
dc.date.available2018-11-22T00:30:39Z
dc.date.issued2018-07
dc.description.abstractThe sleeping sickness parasite Trypanosoma brucei has a complex life cycle, alternating between a mammalian host and the tsetse fly vector. A tightly controlled developmental programme ensures parasite transmission between hosts as well as survival within them and involves strict regulation of mitochondrial activities. In the glucose-rich bloodstream, the replicative 'slender' stage is thought to produce ATP exclusively via glycolysis and uses the mitochondrial F1FO-ATP synthase as an ATP hydrolysis-driven proton pump to generate the mitochondrial membrane potential (ΔΨm). The 'procyclic' stage in the glucose-poor tsetse midgut depends on mitochondrial catabolism of amino acids for energy production, which involves oxidative phosphorylation with ATP production via the F1FO-ATP synthase. Both modes of the F1FO enzyme critically depend on FO subunit a, which is encoded in the parasite's mitochondrial DNA (kinetoplast or kDNA). Comparatively little is known about mitochondrial function and the role of kDNA in non-replicative 'stumpy' bloodstream forms, a developmental stage essential for disease transmission. Here we show that the L262P mutation in the nuclear-encoded F1 subunit γ that permits survival of 'slender' bloodstream forms lacking kDNA ('akinetoplastic' forms), via FO-independent generation of ΔΨm, also permits their differentiation into stumpy forms. However, these akinetoplastic stumpy cells lack a ΔΨm and have a reduced lifespan in vitro and in mice, which significantly alters the within-host dynamics of the parasite. We further show that generation of ΔΨm in stumpy parasites and their ability to use α-ketoglutarate to sustain viability depend on F1-ATPase activity. Surprisingly, however, loss of ΔΨm does not reduce stumpy life span. We conclude that the L262P γ subunit mutation does not enable FO-independent generation of ΔΨm in stumpy cells, most likely as a consequence of mitochondrial ATP production in these cells. In addition, kDNA-encoded genes other than FO subunit a are important for stumpy form viability.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.32944
dc.identifier.eissn1553-7374
dc.identifier.issn1553-7366
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285590
dc.languageeng
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttp://dx.doi.org/10.1371/journal.ppat.1007195
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectDNA, Kinetoplast
dc.subjectDNA, Mitochondrial
dc.subjectHost-Parasite Interactions
dc.subjectMice
dc.subjectTrypanosoma brucei brucei
dc.subjectTrypanosomiasis, African
dc.titleMitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei.
dc.typeArticle
dcterms.dateAccepted2018-07-02
prism.issueIdentifier7
prism.publicationDate2018
prism.publicationNamePLoS Pathog
prism.startingPagee1007195
prism.volume14
rioxxterms.licenseref.startdate2018-07-18
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1371/journal.ppat.1007195

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