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PMID: 23290137 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.

Cell stem cell ·Vol. 12 ·No. 1 ·2013-01-03 ·Pages 62-74

Yu WM, Liu X, Shen J, Jovanovic O, Pohl EE, Gerson SL, Finkel T, Broxmeyer HE, Qu CK

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.

MeSH Terms
Animals Cell Cycle/genetics,physiology Cell Differentiation/genetics,physiology Cells, Cultured Hematopoietic Stem Cells/cytology,metabolism Ion Channels/genetics,metabolism Mice Mice, Knockout Mitochondrial Proteins/genetics,metabolism PTEN Phosphohydrolase/genetics,metabolism Uncoupling Protein 2
Chemicals
Ion Channels Mitochondrial Proteins Ucp2 protein, mouse Uncoupling Protein 2 Ptpmt1 protein, mouse PTEN Phosphohydrolase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Yu Wen-Mei
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.
Liu Xia
Shen Jinhua
Jovanovic Olga
Pohl Elena E
Gerson Stanton L
Finkel Toren
Broxmeyer Hal E
Qu Cheng-Kui
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2012.11.022
Published
2013-01-03
Pages
62-74
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC3632072
Subset
IM
Grants
NIDDK NIH HHS · DK092722 · United States
NIDDK NIH HHS · R01 DK092722 · United States
NHLBI NIH HHS · HL068212 · United States
NHLBI NIH HHS · R01 HL112669 · United States
NHLBI NIH HHS · K18 HL095657 · United States
NHLBI NIH HHS · HL095657 · United States
NHLBI NIH HHS · R01 HL068212 · United States
Corrections
CommentIn
PMID: 23290130
CommentIn
PMID: 23340568
External Links
PubMed source DOI: 10.1016/j.stem.2012.11.022 PMC Full Text View journal details
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