National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Mol Biol Cell. 2020 Jul 1;31(14):1538-1549. doi: 10.1091/mbc.E19-10-0560. Epub 2020 May 6.
A metabolic transition from glycolysis to oxidative phosphorylation is often associated with differentiation of many types of stem cells. However, the link between mitochondrial respiration and stem cells' behavior is not fully understood. We genetically disrupted electron transport chain (ETC) complexes in the intestinal stem cells (ISCs) of . We found that ISCs carrying impaired ETC proliferated much more slowly than normal and produced very few enteroblasts, which failed to further differentiate into enterocytes. One of the main impediments to ISC proliferation and lineage specification appeared to be abnormally elevated forkhead box O (FOXO) signaling in the ETC-deficient ISCs, as genetically suppressing the signaling pathway partially restored the number of enterocytes. Contrary to common belief, reactive oxygen species (ROS) accumulation did not appear to mediate the ETC mutant phenotype. Our results demonstrate that mitochondrial respiration is essential for ISC proliferation and lineage specification in vivo and acts at least partially by repressing endogenous FOXO signaling.
从糖酵解到氧化磷酸化的代谢转变通常与许多类型的干细胞分化有关。然而，线粒体呼吸与干细胞行为之间的联系还不完全清楚。我们在秀丽隐杆线虫的肠干细胞（ISCs）中遗传破坏了电子传递链（ETC）复合物。我们发现，携带受损 ETC 的 ISC 增殖速度比正常情况下慢得多，并且产生的肠母细胞很少，这些细胞无法进一步分化为肠细胞。ETC 缺陷型 ISC 中叉头框 O（FOXO）信号的异常升高似乎是 ISC 增殖和谱系特化的主要障碍之一，因为遗传抑制该信号通路部分恢复了肠细胞的数量。与普遍看法相反，活性氧（ROS）的积累似乎并没有介导 ETC 突变表型。我们的结果表明，线粒体呼吸对于秀丽隐杆线虫 ISC 的增殖和谱系特化是必不可少的，它至少部分通过抑制内源性 FOXO 信号来发挥作用。
