Jiang 2024 Nat Metab

Jiang S, Yuan T, Rosenberger FA, Mourier A, Dragano NRV, Kremer LS, Rubalcava-Gracia D, Hansen FM, Borg M, Mennuni M, Filograna R, Alsina D, Misic J, Koolmeister C, Papadea P, de Angelis MH, Ren L, Andersson O, Unger A, Bergbrede T, Di Lucrezia R, Wibom R, Zierath JR, Krook A, Giavalisco P, Mann M, Larsson NG (2024) Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity. Nat Metab [Epub ahead of print]. https://doi.org/10.1038/s42255-024-01038-3

» PMID: 38689023 Open Access

Jiang Shan, Yuan Taolin, Rosenberger Florian A, Mourier Arnaud, Dragano Nathalia RV, Kremer Laura S, Rubalcava-Gracia Diana, Hansen Fynn M, Borg Melissa, Mennuni Mara, Filograna Roberta, Alsina David, Misic Jelena, Koolmeister Camilla, Papadea Polyxeni, de Angelis Martin Hrabe, Ren Lipeng, Andersson Olov, Unger Anke, Bergbrede Tim, Di Lucrezia Raffaella, Wibom Rolf, Zierath Juleen R, Krook Anna, Giavalisco Patrick, Mann Matthias, Larsson Nils-Goeran (2024) Nat Metab

Abstract: The oxidative phosphorylation system in mammalian mitochondria plays a key role in transducing energy from ingested nutrients. 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 growth. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT) 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.

• Bioblast editor: Plangger M • O2k-Network Lab: FR Bordeaux Mourier A, SE Stockholm Larsson NG

Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Obesity, Other 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S, Gp, Other combinations  HRR: Oxygraph-2k 

2024-05