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

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

doi:10.1016/j.stem.2024.02.004

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

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. ScaddenKeisuke Ito

Cell Biology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	359-377.e10
Journal	Cell Stem Cell
Volume	31
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2024.02.004
State	Published - Mar 7 2024

Keywords

HSC self-renewal
NADPH
cholesterol
exosomes
extracellular vesicles
fate determination
fatty acid oxidation
hematopoietic stem cell
metabolism
mitochondria

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2024.02.004

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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., ... Ito, K. (2024). A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate. Cell Stem Cell, 31(3), 359-377.e10. https://doi.org/10.1016/j.stem.2024.02.004

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, FM, Finkel, T, Lin, CP, Zavan, B, Pinton, P, Georgakoudi, I, Romualdi, C, Scadden, DT & Ito, K 2024, 'A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate', Cell Stem Cell, vol. 31, no. 3, pp. 359-377.e10. https://doi.org/10.1016/j.stem.2024.02.004

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

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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T1 - A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate

AU - Bonora, Massimo

AU - Morganti, Claudia

AU - van Gastel, Nick

AU - Ito, Kyoko

AU - Calura, Enrica

AU - Zanolla, Ilaria

AU - Ferroni, Letizia

AU - Zhang, Yang

AU - Jung, Yookyung

AU - Sales, Gabriele

AU - Martini, Paolo

AU - Nakamura, Takahisa

AU - Lasorsa, Francesco Massimo

AU - Finkel, Toren

AU - Lin, Charles P.

AU - Zavan, Barbara

AU - Pinton, Paolo

AU - Georgakoudi, Irene

AU - Romualdi, Chiara

AU - Scadden, David T.

AU - Ito, Keisuke

PY - 2024/3/7

Y1 - 2024/3/7

N2 - 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.

AB - 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.

KW - HSC self-renewal

KW - NADPH

KW - cholesterol

KW - exosomes

KW - extracellular vesicles

KW - fate determination

KW - fatty acid oxidation

KW - hematopoietic stem cell

KW - metabolism

KW - mitochondria

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JO - Cell Stem Cell

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

Abstract

Keywords

ASJC Scopus subject areas

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