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

Bonora, Massimo;Morganti, Claudia;van Gastel, Nick;Ito, Kyoko;Ito, Keisuke;et.al.
(2024) Cell Stem Cell — Vol. 31, n° 3, p. 359-377 (2024)

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Authors
  • Bonora, Massimo
    Co-first author
  • Morganti, Claudia
    Co-first author
  • van Gastel, NickUCLouvain
    Co-first author
  • Ito, Kyoko
    Author
  • Ito, Keisuke
    Author
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Abstract
(en) 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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Bonora, M., Morganti, C., van Gastel, N., Ito, K., Calura, E., Zanolla, I., Ferroni, L., Zhang, Y., Jung, Y., Sales, G., Martini, P., Nakamura, T., Lasorsa, F. M., Finkel, T., Lin, C. P., Zavan, B., Pinton, P., Georgakoudi, I., Romualdi, C., et al. (2024). A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate. Cell Stem Cell, 31(3), 359-377. https://doi.org/10.1016/j.stem.2024.02.004 (Original work published 2024)