Stem Cell Bioenergetics: A Novel Regulatory Mechanism For p107 in Adipocyte Lineage Fates

The transcriptional co-repressor p107 has previously been shown to determine the metabolic fate of differentiated mesenchymal stem cells and their progenitors in a cell autonomous manner. Importantly, our new data shows that p107 influences stem cell fate decisions by its nuclear re-localization that results in regulating the bioenergetic status of the cells during G0/G1 phase of the cell cycle. In particular, p107 depleted primary stem and progenitor cells at G0/G1 undergo profound metabolic alterations including anaerobic glycolysis and significantly increased respiration. Our results show that p107 KD and KO stem cells and progenitors have an inefficient malate-aspartate shuttle, which decreases the availability of NADH into the mitochondria. Additionally, we found significantly elevated levels of two enzymes that enhance glycolysis, LDHa and PDK2. The effect of bioenergetics on adipocyte lineage fates is evident from inhibition of anaerobic glycolysis, which prevented the brown-type differentiation potential of p107 KD stem cell lines.