Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions
Open accessAbstract
Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation.
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Fumarate affects young HSC function and might restore defects in aged HSCs.
“fumarate affects young HSC function126, and might restore defects in aged HSCs.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [126]
Fumarate impacts young HSC function.
“For example, fumarate, which impacts young HSC function126, might also have beneficial effects on aged HSCs (although this has not been tested).”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [126]
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- Authors
- Guitart, A. V., Panagopoulou, T. I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R. N., van de Lagemaat, L. N., Morgan, M., Giles, P., Sas, Z., Gonzalez, M. V., Lawson, H., Paris, J., Edwards-Hicks, J., Schaak, K., Subramani, C., Gezer, D., Armesilla-Diaz, A., Wills, J., Easterbrook, A., Coman, D., So, C. W. E., O’Carroll, D., Vernimmen, D., Rodrigues, N. P., Pollard, P. J., Morton, N. M., Finch, A., & Kranc, K. R.
- Affiliations
- MRC Centre for Regenerative Medicine (GB)
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK 1
- The Queen's Medical Research Institute (GB)
- Wales Gene Park (GB)
- Edinburgh Cancer Research (GB)
- Mater Private Hospital (AU)
- Children's Health Queensland Hospital and Health Service (AU)
- King's College London (GB)
- Roslin Institute (GB)
- Cardiff University (GB)
- Corresponding author
- Kranc, Kamil R.
- ORCID
- Guitart, Amelie V.
- Panagopoulou, Theano I.
- Villacreces, Arnaud
- Sepulveda, Catarina
- Allen, Lewis
- Carter, Roderick N.
- Morgan, Marcos
- Giles, Peter
- Sas, Zuzanna
- Lawson, Hannah
- Paris, Jasmin
- Edwards-Hicks, Joy
- Schaak, Katrin
- Subramani, Chithra
- Gezer, Deniz
- Armesilla-Diaz, Alejandro
- Wills, Jimi
- Easterbrook, Aaron
- Coman, David
- So, Chi Wai Eric
- Vernimmen, Douglas
- Rodrigues, Neil P.
- Pollard, Patrick J.
- Morton, Nicholas M.
- Finch, Andrew
- Kranc, Kamil R.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2017-02-15
- Volume
- 214
- Issue
- 3
- Pages
- 719-735
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5339674
- OpenAlex
- W2588146519
- Cited by
- 86
- References
- 71
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 10 · 2023: 13 · 2022: 10 · 2021: 15 · 2020: 9 · 2019: 8 · 2018: 3 · 2017: 6
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Griffith Research Online (submittedVersion, cc-by)
- Funders
- Kay Kendall Leukaemia Fund
- Cancer Research UK
- Bloodwise
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- fumarate hydratase, hematopoietic stem cells, fumarate accumulation, TCA cycle, mitochondrial respiration, hematopoiesis, leukemia-initiating cells, lymphoid differentiation, stem cell self-renewal
- MeSH terms
- Animals, Female, Fumarate Hydratase, Fumarates, Hematopoiesis, Hematopoietic Stem Cells, Histones, Mice, Inbred C57BL, Mitochondria, Oxygen Consumption, Leukemia, Myeloid, Acute, NF-E2-Related Factor 2, Mice
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