Advanced

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging.

Norddahl, Gudmundur LU ; Pronk, Kees-Jan LU ; Wahlestedt, Martin LU ; Sten, Gerd LU ; Nygren, Jens LU ; Ugale, Amol LU ; Sigvardsson, Mikael LU and Bryder, David LU (2011) In Cell Stem Cell 8(5). p.499-510
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Stem Cell
volume
8
issue
5
pages
499 - 510
publisher
Cell Press
external identifiers
  • wos:000290927600011
  • pmid:21549326
  • scopus:79955698235
ISSN
1934-5909
DOI
10.1016/j.stem.2011.03.009
language
English
LU publication?
yes
id
72695e5a-7cbc-4d2b-9308-9373051b5167 (old id 1973088)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21549326?dopt=Abstract
date added to LUP
2011-06-07 14:29:02
date last changed
2017-09-03 04:48:15
@article{72695e5a-7cbc-4d2b-9308-9373051b5167,
  abstract     = {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.},
  author       = {Norddahl, Gudmundur and Pronk, Kees-Jan and Wahlestedt, Martin and Sten, Gerd and Nygren, Jens and Ugale, Amol and Sigvardsson, Mikael and Bryder, David},
  issn         = {1934-5909},
  language     = {eng},
  number       = {5},
  pages        = {499--510},
  publisher    = {Cell Press},
  series       = {Cell Stem Cell},
  title        = {Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging.},
  url          = {http://dx.doi.org/10.1016/j.stem.2011.03.009},
  volume       = {8},
  year         = {2011},
}