A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.

Cell stem cell Pub Date : 2024-03-07 DOI:10.1016/j.stem.2024.02.004

Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito

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Abstract

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.

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线粒体 NADPH-胆固醇轴调节细胞外囊泡的生物生成，支持造血干细胞的命运。

线粒体脂肪酸氧化（FAO）是造血干细胞自我更新的必要条件；然而，线粒体代谢控制造血干细胞命运的机制仍然未知。在这里，我们发现在造血干细胞系中，造血干细胞拥有最大的线粒体NADPH池，这是造血干细胞正常命运和平衡所必需的。造血干细胞转录组的生物信息学分析、生化试验以及 FAO 的基因失活均表明，FAO 产生的 NADPH 可促进造血干细胞中胆固醇的合成。干扰 FAO 会扰乱线粒体 NADPH 在单个造血干细胞分裂时向相应子细胞的分离。重要的是，我们发现 FAO-NADPH- 胆固醇轴驱动着造血干细胞中细胞外囊泡（EV）的生物生成和释放，而抑制 EV 信号传导会损害造血干细胞的自我更新。这些数据揭示了线粒体 NADPH- 胆固醇轴对造血稳态所需的 EV 生物发生的作用，并强调了造血干细胞命运决定的非随机性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cell stem cell

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