MFN2型
细胞生物学
NFAT公司
生物
干细胞
造血
线粒体
内质网
线粒体融合
移植
遗传学
转录因子
线粒体DNA
基因
医学
外科
作者
Larry L. Luchsinger,Mariana Justino de Almeida,David Corrigan,Melanie Mumau,Hans-Willem Snoeck
出处
期刊:Nature
[Springer Nature]
日期:2016-01-20
卷期号:529 (7587): 528-531
被引量:197
摘要
Haematopoietic stem cells (HSCs), which sustain production of all blood cell lineages, rely on glycolysis for ATP production, yet little attention has been paid to the role of mitochondria. Here we show in mice that the short isoform of a critical regulator of HSCs, Prdm16 (refs 4, 5), induces mitofusin 2 (Mfn2), a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca(2+), an effect mediated through its endoplasmic reticulum-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat). Nfat inhibition rescued the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. These findings provide a mechanism underlying clonal heterogeneity among HSCs and may lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation.
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