Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle

A functional electron transport chain (ETC) is crucial for maintaining bioenergetic and biosynthetic processes. Accordingly, inhibition of the ETC decreases proliferation in cancer cells. Intriguingly, ETC blockade does not seem to impair stem cell proliferation, but it remains unknown 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 essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the high metabolic plasticity of skeletal stem and progenitor cells allow them to bypass ETC blockade and preserve their self-renewal.