Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

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 de Cózar; Mike Gerards; Mikael Parhiala; Reinald Pamplona; Howard T Jacobs; Priit Jõers

doi:10.1371/journal.pgen.1008410

Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

PLoS Genet. 2019 Oct 4;15(10):e1008410. doi: 10.1371/journal.pgen.1008410. eCollection 2019 Oct.

Authors

Diana Bahhir¹, Cagri Yalgin^{2

3}, Liina Ots¹, Sampsa Järvinen³, Jack George³, Alba Naudí⁴, Tatjana Krama^{5

6}, Indrikis Krams^{5

7

8}, Mairi Tamm¹, Ana Andjelković³, Eric Dufour³, Jose M González de Cózar³, Mike Gerards^{3

9}, Mikael Parhiala³, Reinald Pamplona⁴, Howard T Jacobs³, Priit Jõers^{1

3}

Affiliations

¹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
² Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
³ Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁴ Experimental Medicine Department, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL-IRBLLEIDA), Lleida, Spain.
⁵ Institute of Ecology and Earth Sciences, University of Tartu, Tartu, Estonia.
⁶ Department of Plant Health, Institute of Agricultural and Environmental Sciences, Estonian University of Life Science, Tartu, Estonia.
⁷ Department of Zoology and Animal Ecology, Faculty of Biology, University of Latvia, Rīga, Latvia.
⁸ Department of Biotechnology, Daugavpils University, Daugavpils, Latvia.
⁹ Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / genetics
Animals
Carbohydrate Metabolism / genetics
Carbohydrates / genetics
Cellular Reprogramming / genetics*
DNA Restriction Enzymes / genetics
DNA, Mitochondrial / genetics*
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / metabolism
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism
Humans
Metabolic Networks and Pathways / genetics
Mitochondria / genetics*
Mitochondria / metabolism
Oxidative Phosphorylation
Oxidative Stress / genetics

Substances

Carbohydrates
DNA, Mitochondrial
Adenosine Triphosphate
DNA Restriction Enzymes

Grants and funding

This 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.