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Somatic cells with a heavy mitochondrial DNA mutational load render iPS cells with distinct differentiation defects.

Wahlestedt, Martin LU ; Ameur, Adam; Moraghebi, Roksana LU ; Norddahl, Gudmundur LU ; Sten, Gerd LU ; Woods, Niels-Bjarne LU and Bryder, David LU (2014) In Stem Cells 32(5). p.1173-1182
Abstract
It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes. By taking advantage of a mutator mouse model with an error-prone mtDNA polymerase, we here investigated the impact of an established mtDNA mutational load with regards to the generation, maintenance and differentiation of induced pluripotent stem (iPS) cells. We demonstrate that somatic cells with a heavy mtDNA mutation burden were amenable for reprogramming into iPS... (More)
It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes. By taking advantage of a mutator mouse model with an error-prone mtDNA polymerase, we here investigated the impact of an established mtDNA mutational load with regards to the generation, maintenance and differentiation of induced pluripotent stem (iPS) cells. We demonstrate that somatic cells with a heavy mtDNA mutation burden were amenable for reprogramming into iPS cells. However, mutator iPS cells displayed delayed proliferation kinetics and harbored extensive differentiation defects. While mutator iPS cells had normal ATP levels and glycolytic activity, the induction of differentiation coincided with drastic decreases in ATP production and a hyperactive glycolysis. These data demonstrate the differential requirements of mitochondrial integrity for pluripotent stem cell self-renewal versus differentiation, and highlight the relevance of assessing the mitochondrial genome when aiming to generate iPS cells with robust differentiation potential. Stem Cells 2014. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Stem Cells
volume
32
issue
5
pages
1173 - 1182
publisher
AlphaMed Press
external identifiers
  • pmid:24446123
  • wos:000334597200012
  • scopus:84898997182
ISSN
1549-4918
DOI
10.1002/stem.1630
language
English
LU publication?
yes
id
76d23b5d-5b81-44d8-b9dd-4bef93315f36 (old id 4290997)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24446123?dopt=Abstract
date added to LUP
2014-02-08 11:24:10
date last changed
2017-10-22 03:21:12
@article{76d23b5d-5b81-44d8-b9dd-4bef93315f36,
  abstract     = {It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes. By taking advantage of a mutator mouse model with an error-prone mtDNA polymerase, we here investigated the impact of an established mtDNA mutational load with regards to the generation, maintenance and differentiation of induced pluripotent stem (iPS) cells. We demonstrate that somatic cells with a heavy mtDNA mutation burden were amenable for reprogramming into iPS cells. However, mutator iPS cells displayed delayed proliferation kinetics and harbored extensive differentiation defects. While mutator iPS cells had normal ATP levels and glycolytic activity, the induction of differentiation coincided with drastic decreases in ATP production and a hyperactive glycolysis. These data demonstrate the differential requirements of mitochondrial integrity for pluripotent stem cell self-renewal versus differentiation, and highlight the relevance of assessing the mitochondrial genome when aiming to generate iPS cells with robust differentiation potential. Stem Cells 2014.},
  author       = {Wahlestedt, Martin and Ameur, Adam and Moraghebi, Roksana and Norddahl, Gudmundur and Sten, Gerd and Woods, Niels-Bjarne and Bryder, David},
  issn         = {1549-4918},
  language     = {eng},
  number       = {5},
  pages        = {1173--1182},
  publisher    = {AlphaMed Press},
  series       = {Stem Cells},
  title        = {Somatic cells with a heavy mitochondrial DNA mutational load render iPS cells with distinct differentiation defects.},
  url          = {http://dx.doi.org/10.1002/stem.1630},
  volume       = {32},
  year         = {2014},
}