An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

Maria Maryanovich; Yehudit Zaltsman; Antonella Ruggiero; Andres Goldman; Liat Shachnai; Smadar Levin Zaidman; Ziv Porat; Karin Golan; Tsvee Lapidot; Atan Gross

doi:10.1038/ncomms8901

An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

Nat Commun. 2015 Jul 29:6:7901. doi: 10.1038/ncomms8901.

Authors

Affiliations

¹ Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
² Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
³ Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
⁴ Department Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

PMID: 26219591
DOI: 10.1038/ncomms8901

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Apoptosis / genetics*
Apoptosis / radiation effects
BH3 Interacting Domain Death Agonist Protein / genetics*
BH3 Interacting Domain Death Agonist Protein / metabolism
Blotting, Western
Cell Cycle / genetics
Cell Differentiation / genetics
Colony-Forming Units Assay
Flow Cytometry
Glycolysis / genetics*
Hematopoiesis / genetics*
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism*
Membrane Potential, Mitochondrial
Mice
Microscopy, Electron, Transmission
Mitochondria / metabolism*
Mitochondria / ultrastructure
Mitochondrial Membrane Transport Proteins / genetics*
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Size
Oxidative Phosphorylation*
Radiation Tolerance / genetics*
Reactive Oxygen Species / metabolism
Real-Time Polymerase Chain Reaction

Substances

BH3 Interacting Domain Death Agonist Protein
Bid protein, mouse
Mitochondrial Membrane Transport Proteins
Mtch2 protein, mouse
Reactive Oxygen Species
Adenosine Triphosphate