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Inhibition of mammalian mtDNA transcription in liver reprograms metabolism to reverse diet-induced obesity and hepatosteatosis

ABSTRACT: The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from different types of ingested nutrients1,2. Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states3. Rewiring of mitochondrial metabolism is intricately linked to common metabolic diseases4–6 and is also necessary to promote tumor growth7–11. Here, we demonstrate that per oral treatment of mice with an inhibitor of mitochondrial transcription (IMT)11 leads to a profound inhibition of mtDNA expression in the liver, which markedly reduces complex I levels of the OXPHOS system, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases that feeds electrons into the ubiquinone (Q) pool remain unaltered or are increased. Deep pProteomics and non-targeted metabolomics analyses of liver reveal that IMT-treatment rewires the OXPHOS system to activates fatty acid oxidation in mice regardless of the diet. Remarkably, treatment of high fat diet (HFD)-fed mice with IMTs rapidly normalizes body weight, reverses hepatosteatosis and restores glucose tolerance. We thus propose a novel treatment principle of obesity and diabetes based on inhibition of mtDNA transcription to accomplish a rewiring of mitochondrial metabolism to favor fatty acid degradation.

INSTRUMENT(S): LTQ

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Mario Oroshi

LAB HEAD: Nils-Göran Larsson

PROVIDER: PXD034771 | Pride | 2024-03-28

REPOSITORIES: Pride

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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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Inhibition of mammalian mtDNA transcription in liver reprograms metabolism to reverse diet-induced obesity and hepatosteatosis

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