Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential

被引:182
作者
Luchsinger, Larry L. [1 ,2 ]
de Almeida, Mariana Justino [1 ,3 ]
Corrigan, David J. [1 ,3 ]
Mumau, Melanie [1 ,3 ]
Snoeck, Hans-Willem [1 ,2 ,3 ]
机构
[1] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA
[2] Columbia Univ, Dept Med, Med Ctr, New York, NY 10032 USA
[3] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA
关键词
MITOCHONDRIAL FISSION; ENDOPLASMIC-RETICULUM; FUSION; EXPRESSION; INHIBITOR;
D O I
10.1038/nature16500
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Haematopoietic stem cells (HSCs), which sustain production of all blood cell lineages(1), rely on glycolysis for ATP production(2,3), 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 Ca2+, an effect mediated through its endoplasmic reticulum-mitochondria tethering activity(6,7), 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 HSCs8-11 and may lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation.
引用
收藏
页码:528 / +
页数:16
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