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Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging
Immunology Section, Institution for Experimental Medical Science, Lund University, Lund, Sweden.
Immunology Section, Institution for Experimental Medical Science, Lund University, Lund, Sweden.
Immunology Section, Institution for Experimental Medical Science, Lund University, Lund, Sweden.
Immunology Section, Institution for Experimental Medical Science, Lund University, Lund, Sweden.
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2011 (English)In: Cell Stem Cell, ISSN 1934-5909, Vol. 8, no 5, 499-510 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Cambridge Mass.: Cell Press , 2011. Vol. 8, no 5, 499-510 p.
Keyword [en]
anemia, animal cell, animal experiment, apoptosis, capacity, cell aging, cell differentiation, cell lineage, controlled study, DNA polymerase, efflux, expression, gene mutation, hematopoiesis, hematopoietic stem cell, lymphocytopenia, mitochondrial DNA, mouse, nonhuman, number, p-glycoprotein, pathways, phenotype, priority journal, proliferation, repopulation, serial transplantation, somatic cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:hh:diva-15096DOI: 10.1016/j.stem.2011.03.009ISI: 000290927600011PubMedID: 21549326Scopus ID: 2-s2.0-79955698235OAI: oai:DiVA.org:hh-15096DiVA: diva2:417675
Available from: 2011-05-17 Created: 2011-05-17 Last updated: 2015-09-21Bibliographically approved

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CiteExportLink to record
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