Somatic cells with a heavy mitochondrial DNA mutational load render induced pluripotent stem cells with distinct differentiation defects.
Stem Cells
; 32(5): 1173-82, 2014 May.
Article
in En
| MEDLINE
| ID: mdl-24446123
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA, Mitochondrial
/
Cell Differentiation
/
Induced Pluripotent Stem Cells
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Stem Cells
Year:
2014
Type:
Article
Affiliation country:
Sweden