title: Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3.
abstract: Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3(-/-) HSC that are defective in their activity. We show that Foxo3(-/-) HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3(-/-) hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3(-/-) HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells.
authors.affiliation: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Rimmelé
authors.affiliation: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Liang
authors.affiliation: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Bigarella
authors.affiliation: Division of Cardiology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Fatih
authors.initials: F
authors.lastname: Kocabas
authors.affiliation: Division of Cardiology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Madhavika N
authors.initials: MN
authors.lastname: Serasinghe
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Chipuk
authors.affiliation: Division of Cardiology, UT Southwestern Medical Center, Dallas, TX, USA Department of Physiology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Hesham
authors.initials: H
authors.lastname: Sadek
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY, USA Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Division of Hematology, Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA saghi.ghaffari@mssm.edu.
authors.forename: Saghi
authors.initials: S
authors.lastname: Ghaffari
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases
keywords: FOXO3; HSC; ROS; metabolism; mitochondria