title: Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential.
abstract: Haematopoietic stem cells (HSCs), which sustain production of all blood cell lineages, rely on glycolysis for ATP production, yet little attention has been paid to the role of mitochondria. Here we show in mice that the short isoform of a critical regulator of HSCs, Prdm16 (refs 4, 5), induces mitofusin 2 (Mfn2), a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca(2+), an effect mediated through its endoplasmic reticulum-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat). Nfat inhibition rescued the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. These findings provide a mechanism underlying clonal heterogeneity among HSCs and may lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Larry L
authors.initials: LL
authors.lastname: Luchsinger
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Mariana Justino
authors.initials: MJ
authors.lastname: de Almeida
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Corrigan
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mumau
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Hans-Willem
authors.initials: HW
authors.lastname: Snoeck
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D022423:Myeloid Cells / Q000166:cytology; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D002118:Calcium