title: Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.
abstract: The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ∼40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Yu
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Jinhua
authors.initials: J
authors.lastname: Shen
authors.forename: Olga
authors.initials: O
authors.lastname: Jovanovic
authors.forename: Elena E
authors.initials: EE
authors.lastname: Pohl
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D017027:Protein Tyrosine Phosphatases
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D051059:PTEN Phosphohydrolase; D000071246:Uncoupling Protein 2; C000604390:Ucp2 protein, mouse; C492433:Ptpmt1 protein, mouse; D017027:Protein Tyrosine Phosphatases