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
Abstract
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.