An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate
An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate
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DOI：
10.1038/ncomms8901
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发表时间：
2015-07-01
影响因子：
16.6
通讯作者：
Gross, Atan
中科院分区：
文献类型：
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作者：
Maryanovich, Maria;Zaltsman, Yehudit;Gross, Atan
干细胞的代谢状态正在成为其命运的重要决定因素。在骨髓中，由细胞内活性氧（ROS）增加触发的造血干细胞（HSC）进入周期对应于从糖酵解到线粒体氧化磷酸化（OXPHOS）的关键代谢转换。在这里，我们表明，线粒体载体同源物2（MTCH 2）的损失增加线粒体OXPHOS，触发HSC和祖细胞进入周期。升高的OXPHOS伴随着线粒体大小的增加、ATP和ROS水平的增加以及对辐射诱导的细胞凋亡的保护。相比之下，BID的磷酸化缺陷突变体，MTCH 2的配体，诱导OXPHOS类似的增加，但具有更高的ROS和降低的ATP水平，并且与对辐射的超敏反应相关。因此，我们的结果表明，MTCH 2是BID下游的线粒体OXPHOS的负调节因子，在维持HSC稳态中不可或缺。
The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.