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Myc regulation of ETC Biogenesis and mtDNA Replication

ABSTRACT: To investigate the important role of Myc in regulating mitochondrial respiration and DNA biogenesis during Drosophila oogenesis, we dissected ovaries with developmental stages from germarium to stage 10 egg chambers from 4-6 day-old w1118 and mycP0/P0 mutant flies. We purified and compared mRNA transcriptome profiles (RNA-seq) in triplicate. We found that the mRNA levels for about 75% components in ETC, heme metabolism, mtDNA replication and translation pathways are decreased in mycP0/P0 mutant. Interestingly, about 85.7% down-regulated mitochondrial genes have predicted Myc binding sites (E-box: CACGTG) in their regulatory regions. Considering that not all E-box are active, it is possible that mitochondrial biogenesis is also indirectly controlled by Myc through a secondary transcriptional regulation. We found that Myc also mediate expression of 48 TFs, 35 of which with predicted E-box in their regulatory regions. Hence, our results indicated that Myc is a master regulator of ETC biogenesis through mtDNA replication and ETC gene expression.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE126997 | GEO | 2019/09/01

REPOSITORIES: GEO

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Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.

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Myc regulation of ETC Biogenesis and mtDNA Replication

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