A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
|---|---|
| Enthalten in: |
Cell stem cell - 31(2024), 3 vom: 07. März, Seite 359-377.e10 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bonora, Massimo [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 23.03.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.stem.2024.02.004 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369479106 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369479106 | ||
| 003 | DE-627 | ||
| 005 | 20240323235255.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240309s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.stem.2024.02.004 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1342.xml |
| 035 | |a (DE-627)NLM369479106 | ||
| 035 | |a (NLM)38458178 | ||
| 035 | |a (PII)S1934-5909(24)00047-X | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bonora, Massimo |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.03.2024 | ||
| 500 | |a Date Revised 23.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a HSC self-renewal | |
| 650 | 4 | |a NADPH | |
| 650 | 4 | |a cholesterol | |
| 650 | 4 | |a exosomes | |
| 650 | 4 | |a extracellular vesicles | |
| 650 | 4 | |a fate determination | |
| 650 | 4 | |a fatty acid oxidation | |
| 650 | 4 | |a hematopoietic stem cell | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a mitochondria | |
| 650 | 7 | |a NADP |2 NLM | |
| 650 | 7 | |a 53-59-8 |2 NLM | |
| 700 | 1 | |a Morganti, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a van Gastel, Nick |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Kyoko |e verfasserin |4 aut | |
| 700 | 1 | |a Calura, Enrica |e verfasserin |4 aut | |
| 700 | 1 | |a Zanolla, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Ferroni, Letizia |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Yookyung |e verfasserin |4 aut | |
| 700 | 1 | |a Sales, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Martini, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Takahisa |e verfasserin |4 aut | |
| 700 | 1 | |a Lasorsa, Francesco Massimo |e verfasserin |4 aut | |
| 700 | 1 | |a Finkel, Toren |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Charles P |e verfasserin |4 aut | |
| 700 | 1 | |a Zavan, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Pinton, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Georgakoudi, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Romualdi, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Scadden, David T |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Keisuke |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell stem cell |d 2007 |g 31(2024), 3 vom: 07. März, Seite 359-377.e10 |w (DE-627)NLM176526269 |x 1875-9777 |7 nnns |
| 773 | 1 | 8 | |g volume:31 |g year:2024 |g number:3 |g day:07 |g month:03 |g pages:359-377.e10 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.stem.2024.02.004 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 31 |j 2024 |e 3 |b 07 |c 03 |h 359-377.e10 | ||