Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

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dc.contributor.authorBahhir, Diana
dc.contributor.authorYalgin, Cagri
dc.contributor.authorOts, Liina
dc.contributor.authorJärvinen, Sampsa
dc.contributor.authorGeorge, Jack
dc.contributor.authorNaudí i Farré, Alba
dc.contributor.authorKrama, Tatjana
dc.contributor.authorKrams, Indrikis
dc.contributor.authorTamm, Mairi
dc.contributor.authorAndjelković, Ana
dc.contributor.authorDufour, Eric
dc.contributor.authorGonzález de Cosar, Jose M.
dc.contributor.authorGerards, Mike
dc.contributor.authorParhiala, Mikael
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorJacobs, Howard T.
dc.contributor.authorJõers, Priit
dc.date.accessioned2020-01-27T10:46:07Z
dc.date.available2020-01-27T10:46:07Z
dc.date.issued2019-10-04
dc.date.updated2020-01-27T10:46:07Z
dc.description.abstractMitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, accompanied by elevated serine synthesis. Cleavage and translocation, the two modes of mtEcoBI action, repressed carbohydrate rmetabolism via two different mechanisms. DNA cleavage activity induced a type II diabetes-like phenotype involving deactivation of Akt kinase and inhibition of pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation by cytonuclear depletion of acetyl-CoA (AcCoA). The associated decrease in the concentrations of ketogenic amino acids also produced downstream effects on physiology and behavior, attributable to decreased neurotransmitter levels. We thus provide evidence for novel signaling pathways connecting mtDNA to metabolism, distinct from its role in supporting OXPHOS.
dc.description.sponsorshipThis work was supported by following grants: Academy of Finland postdoctoral grant nr. 132997 and exploratory research grant nr. PUT573 from Estonian Research Council to Priit Jõers; Academy Professorship (255365) and Centre of Excellence grants (272376 and 307431) by Academy of Finland to Howard T Jacobs; Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250), and by FEDER funds from European Union (“A way to build Europe”) to Reinald Pamplona; Vilho Rossin Fund (Finnish Cultural Foundation) grant to Ana Andjelković; Estonian Research Council grant nr. PUT1223 and Latvian Council of Science grant nr. lzp-2018/1-0393 to Indrikis Krams, IUT36-2 to Tatjana Krama; and AFM grant nr. 17424 to Eric Dufour. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1008410
dc.identifier.idgrec029377
dc.identifier.issn1553-7404
dc.identifier.urihttp://hdl.handle.net/10459.1/67882
dc.language.isoeng
dc.publisherPublic Library of Science
dc.relationinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-099200-B-I00/ES/NEUROLIPIDOMICA DEL ENVEJECIMIENTO CEREBRAL HUMANO/
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1371/journal.pgen.1008410
dc.relation.ispartofPlos Genetics, 2019, vol. 15, núm. 10: e1008410, p. 1-31
dc.rightscc-by (c) Bahhir, Diana et al., 2019
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/es/
dc.subject.otherADN mitocondrial
dc.titleManipulating mtDNA in vivo reprograms metabolism via novel response mechanisms
dc.typeinfo:eu-repo/semantics/article
dc.type.versionpublishedVersion
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