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Publication type: Journal Article
Document type: Full Paper

Year: 2013

Author(s): Yu, WM; Liu, X; Shen, J; Jovanovic, O; Pohl, EE; Gerson, SL; Finkel, T; Broxmeyer, HE; Qu, CK

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

Source: Cell Stem Cell. 2013; 12(1):62-74



Authors Vetmeduni Vienna:

Jovanovic Olga
Pohl Elena

Vetmed Research Units
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology and Biophysics


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.

Keywords Pubmed: Animals
Cell Cycle/genetics
Cell Cycle/physiology
Cell Differentiation/genetics
Cell Differentiation/physiology*
Cells, Cultured
Hematopoietic Stem Cells/cytology*
Hematopoietic Stem Cells/metabolism*
Ion Channels/genetics
Ion Channels/metabolism
Mice
Mice, Knockout
Mitochondrial Proteins/genetics
Mitochondrial Proteins/metabolism
PTEN Phosphohydrolase/genetics
PTEN Phosphohydrolase/metabolism*


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