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A bstract   Fanconi anemia (FA) is an inherited bone marrow (BM) failure syndrome, presumably resulting from defects in hematopoietic stem cells (HSCs). Normal HSCs depend more on glycolysis than on oxidative phosphorylation (OXPHOS) for energy production. Here, we show that FA HSCs are more sensitive to the respiration inhibitor NaN3 treatment than to glycolytic inhibitor 2‐deoxy‐ d ‐glucose (2‐DG), indicating more dependence on OXPHOS. FA HSCs undergo glycolysis‐to‐OXPHOS switch in response to oxidative stress through a p53‐dependent mechanism. Metabolic stresses induce upregulation of p53 metabolic targets in FA HSCs. Inactivation of p53 in FA HSCs prevents glycolysis‐to‐OXPHOS switch. Furthermore, p53‐deficient FA HSCs are more sensitive to 2‐DG‐mediated metabolic stress. Finally, oxidative stress‐induced glycolysis‐to‐OXPHOS switch is mediated by synthesis of cytochrome c oxidase 2 (SCO2). These findings demonstrate p53‐mediated OXPHOS function as a compensatory alteration in FA HSCs to ensure a functional but mildly impaired energy metabolism and suggest a cautious approach to manipulating p53 signaling in FA. S tem  C ells   2016;34:960–971

SCO2 Mediates Oxidative Stress‐Induced Glycolysis to Oxidative Phosphorylation Switch in Hematopoietic Stem Cells