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

Wen Mei Yu, Xia Liu, Jinhua Shen, Olga Jovanovic, Elena E. Pohl, Stanton L. Gerson, Toren Finkel, Hal E. Broxmeyer, Cheng Kui Qu

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246 Scopus citations


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.

Original languageEnglish
Pages (from-to)62-74
Number of pages13
JournalCell Stem Cell
Issue number1
StatePublished - Jan 3 2013

Bibliographical note

Funding Information:
We are grateful to Dr. Thomas Graf at the Center for Genomic Regulation and ICREA, Spain, for Vav1-Cre transgenic mice; and Dr. Jaburek and Dr. Jezek at Academy of Sciences, Prague, Czech Republic, for providing us with E. coli inclusion bodies containing recombinant hUCP2. This work was supported by National Institutes of Health grants DK092722, HL068212, and HL095657 (to C.K.Q.) and the German Research Foundation grant Po 524/5-1 (to E.E.P).

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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