Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

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 restri...

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Detalhes bibliográficos
Autores: 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
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/67882
Acesso em linha:https://doi.org/10.1371/journal.pgen.1008410
http://hdl.handle.net/10459.1/67882
Access Level:acceso abierto
Palavra-chave:ADN mitocondrial
Descrição
Resumo: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.

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