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Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

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.

SUBMITTER: Bahhir D

PROVIDER: S-EPMC6795474 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

Bahhir Diana D Yalgin Cagri C Ots Liina L Järvinen Sampsa S George Jack J Naudí Alba A Krama Tatjana T Krams Indrikis I Tamm Mairi M Andjelković Ana A Dufour Eric E González de Cózar Jose M JM Gerards Mike M Parhiala Mikael M Pamplona Reinald R Jacobs Howard T HT Jõers Priit P

PLoS genetics 20191004 10

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 lipi ...[more]

PMID: 31584940

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Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

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Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

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