title: An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate.
abstract: The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Maryanovich
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Zaltsman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ruggiero
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Andres
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Shachnai
authors.affiliation: Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Smadar Levin
authors.initials: SL
authors.lastname: Zaidman
authors.affiliation: Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.affiliation: Department Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Karin
authors.initials: K
authors.lastname: Golan
authors.affiliation: Department Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Atan
authors.initials: A
authors.lastname: Gross
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D006019:Glycolysis / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D053142:Mitochondrial Size; D010085:Oxidative Phosphorylation; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; C550380:Mtch2 protein, mouse; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate