Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

Autoři: Diana Bahhir aff001;  Cagri Yalgin aff002;  Liina Ots aff001;  Sampsa Järvinen aff003;  Jack George aff003;  Alba Naudí aff004;  Tatjana Krama aff005;  Indrikis Krams aff005;  Mairi Tamm aff001;  Ana Andjelković aff003;  Eric Dufour aff003;  Jose M. González de Cózar aff003;  Mike Gerards aff003;  Mikael Parhiala aff003;  Reinald Pamplona aff004;  Howard T. Jacobs aff003;  Priit Jõers aff001
Působiště autorů: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia aff001;  Institute of Biotechnology, University of Helsinki, Helsinki, Finland aff002;  Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland aff003;  Experimental Medicine Department, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL-IRBLLEIDA), Lleida, Spain aff004;  Institute of Ecology and Earth Sciences, University of Tartu, Tartu, Estonia aff005;  Department of Plant Health, Institute of Agricultural and Environmental Sciences, Estonian University of Life Science, Tartu, Estonia aff006;  Department of Zoology and Animal Ecology, Faculty of Biology, University of Latvia, Rīga, Latvia aff007;  Department of Biotechnology, Daugavpils University, Daugavpils, Latvia aff008;  Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands aff009
Vyšlo v časopise: Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008410
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008410


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 decease 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.

Klíčová slova:

Carbohydrates – Drosophila melanogaster – Larvae – Mitochondria – Mitochondrial DNA – Protein metabolism – Pyruvate – Acetylation


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