Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 20092, China; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
Cell Rep. 2020 Nov 24;33(8):108423. doi: 10.1016/j.celrep.2020.108423.
In many tissues, stem cell (SC) proliferation is dynamically adjusted to regenerative needs. How SCs adapt their metabolism to meet the demands of proliferation and how changes in such adaptive mechanisms contribute to age-related dysfunction remain poorly understood. Here, we identify mitochondrial Ca uptake as a central coordinator of SC metabolism. Live imaging of genetically encoded metabolite sensors in intestinal SCs (ISCs) of Drosophila reveals that mitochondrial Ca uptake transiently adapts electron transport chain flux to match energetic demand upon proliferative activation. This tight metabolic adaptation is lost in ISCs of old flies, as declines in mitochondrial Ca uptake promote a "Warburg-like" metabolic reprogramming toward aerobic glycolysis. This switch mimics metabolic reprogramming by the oncogene Ras and enhances ISC hyperplasia. Our data identify a critical mechanism for metabolic adaptation of tissue SCs and reveal how its decline sets aging SCs on a metabolic trajectory reminiscent of that seen upon oncogenic transformation.
在许多组织中，干细胞 (SC) 的增殖是动态调节以适应再生需求的。SCs 如何调整其代谢以满足增殖的需求，以及这种适应性机制的变化如何导致与年龄相关的功能障碍，这些仍然知之甚少。在这里，我们确定线粒体 Ca 摄取是 SC 代谢的核心协调者。在果蝇的肠道干细胞 (ISCs) 中，对遗传编码代谢物传感器的实时成像显示，线粒体 Ca 摄取会短暂地适应电子传递链通量，以在增殖激活时匹配能量需求。这种紧密的代谢适应在老年果蝇的 ISCs 中丧失，因为线粒体 Ca 摄取的下降促进了向有氧糖酵解的“Warburg 样”代谢重编程。这种转变模拟了致癌基因 Ras 的代谢重编程，并增强了 ISC 的过度增生。我们的数据确定了组织 SC 代谢适应的关键机制，并揭示了其下降如何使衰老的 SC 沿着类似于致癌转化时看到的代谢轨迹发展。
