title: Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal.
abstract: Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa.
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Radomir
authors.initials: R
authors.lastname: Kratchmarov
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Nish
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Wen-Hsuan W
authors.initials: WW
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Nyanza J
authors.initials: NJ
authors.lastname: Rothman
authors.affiliation: Department of Medicine and Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Larry L
authors.initials: LL
authors.lastname: Luchsinger
authors.affiliation: Department of Pathology and Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: Vanderbilt Centre for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: Department of Medicine and Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Hans-Willem
authors.initials: HW
authors.lastname: Snoeck
authors.affiliation: Department of Microbiology and Immunology and Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: sr2978@cumc.columbia.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D000071161:Forkhead Box Protein O1 / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis; D006410:Hematopoiesis / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism*; D008660:Metabolism / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D000071161:Forkhead Box Protein O1; D050835:Interferon Regulatory Factors; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D000099218:Interferon Regulatory Factor-4; C467200:Foxo1 protein, mouse; C546843:mTOR protein, mouse
keywords: Pax5; TCF1; Warburg effect; asymmetric cell division; self-renewal; stem cell