Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.
Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.
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DOI：
10.1016/j.stem.2012.11.022
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发表时间：
2013-01-03
期刊：
影响因子：
23.9
通讯作者：
Qu, Cheng-Kui
中科院分区：
文献类型：
--
作者：
Yu, Wen-Mei;Liu, Xia;Shen, Jinhua;Jovanovic, Olga;Pohl, Elena E.;Gerson, Stanton L.;Finkel, Toren;Broxmeyer, Hal E.;Qu, Cheng-Kui
线粒体代谢与造血干细胞(HSC)自我更新和分化的调节和协调还不完全清楚。在这里，我们报道了PTPMT1，一种类似PTEN的线粒体磷酸酶，在可诱导的或造血细胞特异的基因敲除小鼠中，由于细胞周期的改变和HSCs的分化受阻而导致造血衰竭。令人惊讶的是，在PTPMT1基因敲除小鼠中，HSC池增加了约40倍。重新引入野生型PTPMT1，但不是催化缺陷的PTPMT1或缺乏线粒体定位的截短PTPMT1，恢复了PTPMT1基因敲除的HSC的分化能力。进一步的分析表明，PTPMT1缺乏改变了线粒体的新陈代谢，PTPMT1的磷脂酰肌醇磷酸底物直接增强了脂肪酸诱导的线粒体解偶联蛋白2的激活。有趣的是，髓系、T淋巴系或B淋巴系祖细胞的PTPMT1缺失并不会导致谱系特异性基因敲除小鼠的任何缺陷。本研究确立了PTPMT1在HSC功能代谢调节中的重要作用。
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.
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影响因子：
3.2
作者：
Mantel, Charlie;Messina-Graham, Steven V.;Broxmeyer, Hal E.
通讯作者：
Broxmeyer, Hal E.
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
4.3
作者：
Beck, Valeri;Jaburek, Martin;Pohl, Elena E.
通讯作者：
Pohl, Elena E.
影响因子：
56.9
作者：
Cheng, T;Rodrigues, N;Scadden, DT
通讯作者：
Scadden, DT
DOI：
10.1006/bbrc.2001.5627
发表时间：
2001-09-21
影响因子：
3.1
作者：
Imamura, K;Ogura, T;Esumi, H
通讯作者：
Esumi, H