Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA.
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; de Duve Institute, UCLouvain, 1200 Brussels, Belgium.
Cell Stem Cell. 2024 Mar 7;31(3):359-377.e10. doi: 10.1016/j.stem.2024.02.004.
Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
线粒体脂肪酸氧化（FAO）对于造血干细胞（HSC）的自我更新至关重要；然而，线粒体代谢控制 HSC 命运的机制尚不清楚。在这里，我们表明，在造血谱系中，HSCs 具有最大的线粒体 NADPH 池，这对于适当的 HSC 细胞命运和体内平衡是必需的。对 HSC 转录组的生物信息学分析、生化测定以及 FAO 的遗传失活都表明，FAO 产生的 NADPH 为 HSCs 中的胆固醇合成提供燃料。干扰 FAO 会在单个 HSC 分裂时扰乱线粒体 NADPH 向相应子细胞的分配。重要的是，我们发现 FAO-NADPH-胆固醇轴驱动 HSCs 中外泌体（EV）的发生和释放，而抑制 EV 信号会损害 HSC 的自我更新。这些数据揭示了 EV 发生所必需的线粒体 NADPH-胆固醇轴的存在，这对于造血体内平衡很重要，并强调了 HSC 命运决定的非随机性。
