Ramalho Sofia, Alkan Ferhat, Prekovic Stefan, Jastrzebski Katarzyna, Barberà Eric Pintó, Hoekman Liesbeth, Altelaar Maarten, de Heus Cecilia, Liv Nalan, Rodríguez-Colman Maria J, Yilmaz Mehmet, van der Kammen Rob, Fedry Juliette, de Gooijer Mark C, Suijkerbuijk Saskia Jacoba Elisabeth, Faller William J, Silva Joana
Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands.
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
Sci Adv. 2025 Jan 10;11(2):eadn9750. doi: 10.1126/sciadv.adn9750. Epub 2025 Jan 8.
Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
肠道干细胞（ISC）面临着将代谢需求与独特的再生功能相结合的挑战。研究表明，代谢与干细胞能力之间存在着复杂的相互作用；然而，这个过程是如何被调控的仍不清楚。通过在肠道类器官中结合核糖体分析和CRISPR筛选，我们确定新生多肽相关复合体（NAC）是这一过程的关键调节因子。我们的研究结果表明，NAC负责将核糖体重新定位到线粒体并调节ISC代谢。在NAC受到抑制时，肠道细胞中线粒体蛋白的导入减少，而这些蛋白是氧化磷酸化所必需的，因此，使细胞能够维持干细胞特性。此外，我们表明NACα的过表达足以驱动线粒体呼吸并促进ISC特性。最终，我们的结果揭示了NAC在调节核糖体定位、线粒体代谢和ISC功能方面的关键作用，为其背后的潜在机制提供了见解。
