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An Alternative Culture Method to Maintain Genomic Hypomethylation of Mouse Embryonic Stem Cells Using MEK Inhibitor PD0325901 and Vitamin C
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mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling

Riikka H Hämäläinen1, Kati J Ahlqvist1, Pekka Ellonen2

  • 1Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.

Cell Reports
|June 2, 2015
PubMed

Insights

Mitochondrial DNA (mtDNA) mutations impair stem cell function and reprogramming. Pluripotent stem cells (PSCs) resist mtDNA mutations, but mutagenesis increases reactive oxygen species (ROS), hindering stemness. Antioxidants partially restore function but can be toxic.

Area of Science:

  • Stem cell biology
  • Mitochondrial genetics
  • Redox signaling

Background:

  • Somatic mtDNA mutagenesis causes stem cell dysfunction and progeria.
  • Reactive oxygen species (ROS)/redox signaling is implicated in this mechanism.

Purpose of the Study:

  • To investigate the impact of mtDNA mutagenesis on pluripotent stem cell (PSC) reprogramming and stemness.
  • To elucidate the role of mitochondrial ROS in PSC function.

Main Methods:

  • Studied mtDNA mutagenesis effects on PSCs.
  • Assessed reprogramming efficiency and self-renewal.
  • Utilized mitochondria-targeted ubiquinone (MitoQ) and N-acetyl-L-cysteine to counteract defects.

Main Results:

  • PSCs actively select against specific mtDNA mutations, maintaining mtDNA integrity.
  • mtDNA mutagenesis increases mitochondrial H2O2, reducing PSC reprogramming and self-renewal.
  • MitoQ and N-acetyl-L-cysteine rescued these defects.
  • PSCs and neural stem cells showed sensitivity to MitoQ toxicity.

Conclusions:

  • Mitochondrial redox signaling is crucial for maintaining normal stem cell function.
  • Stem cell compartments require careful safety assessment for new antioxidants.
  • PSCs possess mechanisms to preserve mtDNA integrity despite glycolytic metabolism.

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