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Jiang, S.* ; Yuan, T.* ; Rosenberger, F.A.* ; Mourier, A.* ; Dragano, N.R.V. ; Kremer, L.* ; Rubalcava-Gracia, D.* ; Hansen, F.M.* ; Borg, M.* ; Mennuni, M.* ; Filograna, R.* ; Alsina, D.* ; Misic, J.* ; Koolmeister, C.* ; Papadea, P.* ; Hrabě de Angelis, M. ; Ren, L.* ; Andersson, O.* ; Unger, A.* ; Bergbrede, T.* ; Di Lucrezia, R.* ; Wibom, R.* ; Zierath, J.R.* ; Krook, A.* ; Giavalisco, P.* ; Mann, M.* ; Larsson, N.G.*

Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.

Nat. Metab., 29 (2024)

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The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3–5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Mitochondrial; Metformin; Phosphorylation; Dinitrophenol; Maintenance

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Pages: 29

Publisher Springer

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants European Molecular Biology Organization (EMBO)
Novo Nordisk Fonden (Novo Nordisk Foundation)
Swedish Cancer Foundation
Vetenskapsrådet (Swedish Research Council)