Glutamine metabolism co‐ordinates the cell‐cycle with cell fate in stem cells

Activation of stem cell proliferation is a critical event in tissue regeneration. The metabolic switch in adult stem cells from the oxidative to the glycolytic mode of carbon utilization is essential for rapid proliferative bursts, but its impact on self-renewal is unclear. During the glycolytic mode of glucose utilization, glutamine-derived carbons drive the mitochondrial TCA cycle. While glutamine is required for stem cell proliferation burst, its role in maintaining stem cell self-renewal property remains unclear. Here, we show that withdrawal or chemical inhibition of mitochondrial glutamine metabolism blunted adult muscle stem cell proliferation, but also reactivated the transcription of self-renewal-associated transcripts, such as Pax7, to reduce stem cell heterogeneity and build the self-renewing stem cell population. Thus, surprisingly, glutamine withdrawal preserved and accentuated the self-renewing stem cell population. This effect of glutamine is mediated via reductive carboxylation of alpha-ketoglutarate. Mechanistically, we extensively show that glutamine inhibited cell-cycle linked self-renewing network during the G2-M phase of cell-cycle to drive the exit from self-renewal during the terminal mitosis phase before differentiation. Thus, we propose that glutamine metabolism plays an unexpected role in building the progenitor population that is uniquely primed for differentiation during tissue regeneration.