Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

• DOI: 10.1371/journal.pgen.1008410
• Publication Date: 2019-10-04T17:30:51Z
• Authors: Diana Bahhir; Cagri Yalgin; Liina Ots; Sampsa Järvinen; Jack George; Alba Naudí; Tatjana Krama; Indrikis Krams; Mairi Tamm; Ana Andjelković; Eric Dufour; Jose M. González ...; Mike Gerards; Mikael Parhiala; Reinald Pamplona; Howard T. Jacobs; Priit Jõers
• Keywords: DYNAMICS; 0301 basic medicine; STRESS; MITOCHONDRIAL-DNA; Carbohydrates; ADN mitocondrial; QH426-470; fysiologia - Genetics; DNA, Mitochondrial; Oxidative Phosphorylation; Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology; developmental biology; 03 medical and health sciences; Adenosine Triphosphate; Genetiikka, kehitysbiologia, fysiologia - Genetics, developmental biology, physiology; Genetics; Animals; Humans; TRANSCRIPTION; Biochemistry, cell and molecular biology; 0303 health sciences; Biokemia; METHYLATION; DNA Restriction Enzymes; Cellular Reprogramming; TRANSLOCATION; Mitochondria; cell and molecular biology; Genetiikka; DELETIONS; DROSOPHILA; Oxidative Stress; MAINTENANCE; Drosophila melanogaster; Diabetes Mellitus, Type 2; solu- ja molekyylibiologia - Biochemistry; physiology; SURVIVAL; Carbohydrate Metabolism; kehitysbiologia; Metabolic Networks and Pathways; Research Article

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 Drosophila using mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results unexpected reprogramming 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 different mechanisms. cleavage activity induced type II diabetes-like phenotype involving deactivation Akt kinase inhibition pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation cytonuclear depletion acetyl-CoA (AcCoA). The associated decrease concentrations ketogenic amino acids also produced downstream physiology behavior, attributable neurotransmitter levels. We thus provide evidence novel signaling pathways connecting mtDNA metabolism, its role supporting