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 supporting bioenergetics and biosynthesis. Accord-ingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell prolifera-tion. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmaco-logical 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 ac-tivity 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.

Automated summary

Stem cells bypass mitochondrial oxidative phosphorylation blockade and maintain self-renewal ability by adjusting metabolic pathways.