6533b82efe1ef96bd12938ac
RESEARCH PRODUCT
Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.
Diana BahhirCagri YalginLiina OtsSampsa JärvinenJack GeorgeAlba NaudíTatjana KramaIndrikis KramsMairi TammAna AndjelkovićEric DufourJose M. González De CózarMike GerardsMikael ParhialaReinald PamplonaHoward T. JacobsPriit Jõerssubject
DYNAMICSLife CyclesSTRESSMITOCHONDRIAL-DNAADN mitocondrialQH426-470BiochemistryOxidative PhosphorylationLarvaeAdenosine TriphosphateTRANSCRIPTIONPost-Translational ModificationEnergy-Producing OrganellesProtein MetabolismOrganic CompoundsDrosophila MelanogasterChemical ReactionsMETHYLATIONEukaryotaAcetylationAnimal ModelsDNA Restriction EnzymesKetonesCellular ReprogrammingMitochondrial DNAMitochondriaTRANSLOCATIONNucleic acidsInsectsChemistryDROSOPHILAExperimental Organism SystemsPhysical SciencesSURVIVALCarbohydrate MetabolismCellular Structures and OrganellesMetabolic Networks and PathwaysResearch ArticlePyruvateArthropodaForms of DNAeducationCarbohydratesBioenergeticsResearch and Analysis MethodsDNA MitochondrialBiokemia solu- ja molekyylibiologia - Biochemistry cell and molecular biologyModel OrganismsGenetiikka kehitysbiologia fysiologia - Genetics developmental biology physiologyGeneticsAnimalsHumansBiology and life sciencesOrganic ChemistryOrganismsChemical CompoundsProteinsDNACell BiologyInvertebratesDELETIONSOxidative StressMetabolismMAINTENANCEDiabetes Mellitus Type 2Animal Studies1182 Biochemistry cell and molecular biologyAcidsDevelopmental Biologydescription
Mitochondria 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-10-01 | PLoS Genetics |