Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts

Alexandra Kukat, Daniel Edgar, Ivana Bratic, Priyanka Maiti, Aleksandra Trifunovic

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

An increase in mtDNA mutation load leads to a loss of critical cells in different tissues thereby contributing to the physiological process of organismal ageing. Additionally, the accumulation of senescent cells that display changes in metabolic function might act in an active way to further disrupt the normal tissue function. We believe that this could be the important link missing in our understanding of the molecular mechanisms of premature ageing in the mtDNA mutator mice. We tested proliferation capacity of mtDNA mutator cells in vitro. When cultured in physiological levels of oxygen (3%) their proliferation capacity is somewhat lower than wild-type cells. Surprisingly, in conditions of increased oxidative stress (20% O2) mtDNA mutator mouse embryonic fibroblasts exhibit continuous proliferation due to spontaneous immortalization, whereas the same conditions promote senescence in wild-type cells. We believe that an increase in aerobic glycolysis observed in mtDNA mutator mice is a major mechanism behind this process. We propose that glycolysis promotes proliferation and allows a fast turnover of metabolites, but also leads to energy crisis due to lower ATP production rate. This could lead to compromised replication and/or repair and therefore, in rare cases, might lead to mutations in tumor suppressor genes and spontaneous immortalization.

Original languageEnglish (US)
Pages (from-to)394-399
Number of pages6
JournalBiochemical and biophysical research communications
Volume409
Issue number3
DOIs
StatePublished - Jun 10 2011
Externally publishedYes

Keywords

  • Aerobic glycolysis
  • Cellular senescence
  • MEFs
  • MtDNA mutator

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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