Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
Nat Commun. 2015 Jul 29;6:7901. doi: 10.1038/ncomms8901.
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.
干细胞的代谢状态正成为决定其命运的一个重要因素。在骨髓中，造血干细胞（HSC）进入细胞周期，是由细胞内活性氧（ROS）的增加触发的，这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（MTCH2）的缺失会增加线粒体 OXPHOS，从而触发 HSC 和祖细胞进入细胞周期。OXPHOS 的增加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凋亡的保护。相比之下，BID 的磷酸化缺陷型突变体，即 MTCH2 的配体，也会导致 OXPHOS 类似的增加，但 ROS 水平更高，ATP 水平更低，并且与对辐射的敏感性增加有关。因此，我们的结果表明，MTCH2 是 BID 下游线粒体 OXPHOS 的负调节剂，对维持 HSC 稳态是必不可少的。
