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.
Cell Stem Cell. 2013 Jan 3;12(1):62-74. doi: 10.1016/j.stem.2012.11.022.
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.
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尚未完全阐明。在这里，我们报告说，在诱导型或造血细胞特异性敲除小鼠中耗尽 PTPMT1（一种类似于 PTEN 的线粒体磷酸酶）会导致造血功能衰竭，这是由于细胞周期的变化和 HSC 分化受阻所致。令人惊讶的是，PTPMT1 敲除小鼠中的 HSC 池增加了约 40 倍。野生型 PTPMT1 的重新引入，但不是催化缺陷型 PTPMT1 或缺乏线粒体定位的截断 PTPMT1，恢复了 PTPMT1 敲除 HSC 的分化能力。进一步的分析表明，PTPMT1 缺乏会改变线粒体代谢，并且 PTPMT1 的磷脂酰肌醇磷酸盐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，从髓样、T 淋巴样或 B 淋巴样祖细胞中耗尽 PTPMT1 不会导致谱系特异性敲除小鼠出现任何缺陷。这项研究确立了 PTPMT1 在 HSC 功能的代谢调节中的关键作用。
