Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle
Guillaume Tournaire,
Shauni Loopmans,
Steve Stegen,
Gianmarco Rinaldi,
Guy Eelen,
Sophie Torrekens,
Karen Moermans,
Peter Carmeliet,
Bart Ghesquière,
Bernard Thienpont,
Sarah-Maria Fendt,
Nick van Gastel,
Geert Carmeliet
Affiliations
Guillaume Tournaire
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
Shauni Loopmans
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
Steve Stegen
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
Gianmarco Rinaldi
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Guy Eelen
Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Sophie Torrekens
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium
Karen Moermans
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium
Peter Carmeliet
Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Bart Ghesquière
Metabolomics Expertise Center, Department of Oncology, KU Leuven/VIB Center for Cancer Biology Leuven, Leuven, Belgium
Bernard Thienpont
Laboratory of Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
Sarah-Maria Fendt
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Nick van Gastel
de Duve Institute, UC Louvain, Brussels, Belgium
Geert Carmeliet
Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium; Corresponding author
Summary: A functional electron transport chain (ETC) is crucial for supporting bioenergetics and biosynthesis. Accordingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell proliferation. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmacological inhibition of complex III of the ETC in skeletal stem and progenitor cells induces glycolysis side pathways and reroutes the tricarboxylic acid (TCA) cycle to regenerate NAD+ and preserve cell proliferation. These metabolic changes also culminate in increased succinate and 2-hydroxyglutarate levels that inhibit Ten-eleven translocation (TET) DNA demethylase activity, thereby preserving self-renewal and multilineage potential. Mechanistically, mitochondrial malate dehydrogenase and reverse succinate dehydrogenase activity proved to be essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the metabolic plasticity of skeletal stem and progenitor cells allows them to bypass ETC blockade and preserve their self-renewal.
