title: Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts.
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% O(2)) 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.
authors.affiliation: Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institute, S-17171 Stockholm, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kukat
authors.forename: Daniel
authors.initials: D
authors.lastname: Edgar
authors.forename: Ivana
authors.initials: I
authors.lastname: Bratic
authors.forename: Priyanka
authors.initials: P
authors.lastname: Maiti
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006019:Glycolysis; D051379:Mice; D008928:Mitochondria / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial