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

Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

Author information

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.

PMID:
31584940
PMCID:
PMC6795474
DOI:
10.1371/journal.pgen.1008410
[Indexed for MEDLINE]
Free PMC Article

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