Accumulating Mitochondrial DNA Mutations Drive Premature Hematopoietic Aging Phenotypes Distinct from Physiological Stem Cell Aging
Open accessAbstract
Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
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The discrepancy between HSC phenotypes in mtDNA mutator mice and chronologically aged animals suggests that mtDNA mutations may not be a primary driver of tissue stem cell aging.
“This discrepancy between HSC phenotypes observed in these animals and those observed in chronologically aged animals suggests that mtDNA mutations may not be a primary driver of tissue stem cell aging103.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [103]
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References 39 · Cited by 249
- Authors
- Norddahl, G. L., Pronk, C. J., Wahlestedt, M., Sten, G., Nygren, J. M., Ugale, A., Sigvardsson, M., & Bryder, D.
- Affiliations
- Lund University (SE)
- Linköping University (SE)
- Corresponding author
- Bryder, David
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 8
- Issue
- 5
- Pages
- 499-510
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2070427701
- Cited by
- 249
- References
- 39
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 19 · 2020: 22 · 2019: 19 · 2018: 16 · 2017: 13 · 2016: 21 · 2015: 21 · 2014: 19 · 2013: 24 · 2012: 11
- FWCI
- 12.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mitochondrial DNA mutations, hematopoietic stem cell aging, hematopoietic defects, anemia, lymphopenia, multilineage differentiation, hematopoietic progenitor cells, aging
- MeSH terms
- DNA Polymerase gamma, Anemia, Animals, Cells, Cultured, Chimera, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Hematopoiesis, Hematopoietic Stem Cells, Lymphopenia, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondria, Mutation, Regeneration, Cellular Senescence, Aging, Premature, Gene Expression Profiling, Mice, Membrane Potential, Mitochondrial, Adult Stem Cells
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