Taken together, these results suggest that in response to oxidative stress, FA HSC/progenitor cells switch their energy metabolism from aerobic glycolysis to OXPHOS. == p53 is upregulated in FA HSCs in response to metabolic stress == The observation that FA HSCs undergo a glycolysis to OXPHOS switch in response to oxidative stress prompted us to investigate the underlying molecular mechanism. cells (HSCs) are a distinct population of pluripotent cells that can self-renew and differentiate into various types of cells of the blood lineage [1]. Under steady physiological conditions, the most primitive HSCs are in a quiescent state and reside in the bone marrow (BM) niche where they preserve the capacity to self-renew and to continue to produce all types of blood cells throughout a prolonged life span without depleting the regenerative cell pool [2, 3]. In response to stress or stimulation, the HSCs can move out of the BM niche, enter the cell cycle and undergo division. In addition , the cycling HSCs may return to the BM niche and regain their quiescent state [4]. Disruption of HSC quiescence prematurely exhausts the stem cell pool and causes hematological failure under various stressors, such as oxidative stress, cell cycling, and aging [5, 6]. Like stem cells in other tissues, HSC employs two main modes of energy production: glycolysis and oxidative phosphorylation (OXPHOS). It has recently been demonstrated that HSCs possess a distinct metabolic profile with a preference for glycolysis rather than OXPHOS [7, 8]. However , how HSCs reprogram their metabolism to maintain functions in response to stressors is not well understood. The tumor suppressor p53 is a master regulator of cell-cycle arrest, apoptosis, senescence, and differentiation, and thus plays a pivotal role in MI-1061 tumorogenesis, cell-death and survival [9, 10]. In addition , p53 is also a central regulator of energy metabolism [11, 12]. p53 regulates energy metabolism at the glycolytic and OXPHOS steps via transcriptional regulation of its downstream genes TP53- induced glycolysis regulator (TIGAR) and synthesis of cytochromecoxidase (SCO2) [13, 14]. On one hand, p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose-2, 6-bisphosphate). On the other hand, p53 positively regulates OXPHOS through upregulation of SCO2, a member of the MI-1061 COX-2 assembly involved in the electron-transport chain. Recently, it has also MI-1061 been shown that p53 has important functions in hematopoiesis regulating HSC quiescence and self-renewal [15, 16]. Interestingly, how p53 can antagonistically regulate two crucial steps of the energy metabolism and the relation of this regulation with the Rabbit polyclonal to INMT role of p53 in HSC homeostasis remains to be elucidated. The ability of HSCs to produce the complete hematopoietic lineages is a major interest in the research of hematopoiesis, and clinically, at the center of stem cell therapy in hematologic diseases including BM failure and leukemia [1, 17]. One of the best studied hematologic disease models is Fanconi anemia (FA), a genetic disorder associated with BM failure, clonal proliferation of hematopoietic stem and progenitor cells, and progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [18, 23]. FA is caused by a deficiency in any of the seventeen FA genes (FANCA-Q) [24, 26], which cooperate in a DNA repair pathway for resolving DNA interstrand cross-link (ICL) encountered during replication or generated by DNA-damaging agents [27, 28]. The effect of FA deficiency on energy metabolism in HSC function has yet to be exploited. In this study, we have demonstrated that FA HSCs are more dependent on OXPHOS and undergo the glycolysis to OXPHOS switch in response to oxidative stress to meet the increased demand for energy through a p53-dependent mechanism. We have also identified SCO2 as a critical effector of p53 in mediating the oxidative stress-induced glycolysis to OXPHOS switch. These findings provide novel insights MI-1061 into not only the mechanistic connection between energy deficit and FA HSC defect, but also the beneficial effect of p53 on FA HSC maintenance. == Materials and Methods == == Animals == Fanca+/andFancc+/mice (C57BL/6: B6, CD45. 2+) were provided by Dr . Madeleine Carreau (Laval.