Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

Thumbnail
View/Open
Issue date
2019-10-04
Author
Bahhir, Diana
Yalgin, Cagri
Ots, Liina
Järvinen, Sampsa
George, Jack
Naudí i Farré, Alba
Krama, Tatjana
Krams, Indrikis
Tamm, Mairi
Andjelković, Ana
Dufour, Eric
González de Cosar, Jose M.
Gerards, Mike
Parhiala, Mikael
Pamplona Gras, Reinald
Jacobs, Howard T.
Jõers, Priit
Suggested citation
Bahhir, Diana; Yalgin, Cagri; Ots, Liina; Järvinen, Sampsa; George, Jack; Naudí i Farré, Alba; ... Jõers, Priit. (2019) . Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms. Plos Genetics, 2019, vol. 15, núm. 10: e1008410, p. 1-31. https://doi.org/10.1371/journal.pgen.1008410.
Impact

Google Scholar logo  Google Scholar
Share
Export to Mendeley
Metadata
Show full item record
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.
URI
http://hdl.handle.net/10459.1/67882
DOI
https://doi.org/10.1371/journal.pgen.1008410
Is part of
Plos Genetics, 2019, vol. 15, núm. 10: e1008410, p. 1-31
Collections
cc-by (c) Bahhir, Diana et al., 2019
Except where otherwise noted, this item's license is described as cc-by (c) Bahhir, Diana et al., 2019