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.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Bahhir D,Yalgin C,Ots L,Järvinen S,George J,Naudí A,Krama T,Krams I,Tamm M,Andjelković A,Dufour E,González de Cózar JM,Gerards M,Parhiala M,Pamplona R,Jacobs HT,Jõers Pdoi
10.1371/journal.pgen.1008410subject
Has Abstractpub_date
2019-10-04 00:00:00pages
e1008410issue
10eissn
1553-7390issn
1553-7404pii
PGENETICS-D-19-00109journal_volume
15pub_type
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