Author:
Jiang Shan,Yuan Taolin,Kremer Laura S,Rosenberger Florian A,Hansen Fynn M,Borg Melissa,Rubalcava-Gracia Diana,Mennuni Mara,Filograna Roberta,Alsina David,Misic Jelena,Koolmeister Camilla,Ren Lipeng,Andersson Olov,Unger Anke,Bergbrede Tim,Lucrezia Raffaella Di,Wibom Rolf,Zierath Juleen R,Krook Anna,Giavalisco Patrick,Mann Matthias,Larsson Nils-Göran
Abstract
SummaryThe oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from 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, 4. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases5, 6and is also necessary to promote tumour growth7–11. Here, we demonstrate thatper oraltreatment with an inhibitor of mitochondrial transcription (IMT)11shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.
Publisher
Cold Spring Harbor Laboratory