Early induction of senescence and immortalization in PGC-1α-deficient mouse embryonic fibroblasts

Oxidative stress is known to induce early replicative senescence. Senescence has been proposed to work as a barrier to immortalization and tumor development. Here, we aimed to evaluate the impact of the loss of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), a master regulator of oxidative metabolism and mitochondrial reactive oxygen species (ROS) generation, on replicative senescence and immortalization in mouse embryonic fibroblasts (MEFs). We found that primary MEFs lacking PGC-1α showed higher levels of ROS than wild-type MEFs at all cell passages tested. The elevated production of ROS was associated with higher levels of oxidative DNA damage and the increased formation of DNA double-strand breaks. Evaluation of the induction of DNA repair systems in response to γ-radiation indicated that the loss of PGC-1α also resulted in a small but significant reduction in their activity. DNA damage induced the early activation of senescence markers, including an increase in the number of β-galactosidase-positive cells, the induction of p53 phosphorylation, and the increase in p16 and p19 protein. These changes were, however, not sufficient to reduce proliferation rates of PGC-1α-deficient MEFs at any cell passage tested. Moreover, PGC-1α-deficient cells escaped replicative senescence. PGC-1α plays an important role in the control of cellular senescence and immortalization. PGC-1α deficient MEFs showed an exacerbated production of ROS compared to PGC-1α+/+ when serially passaged, these increased ROS levels were associated with the early induction of senescence markers. However, PGC-1α deficient MEFs maintained similar proliferation rates to those of PGC-1α+/+ MEFs and immortalized earlier than PGC-1α+/+ MEFs. [Display omitted] •We evaluated the role of PGC-1α on the induction of cellular senescence and immortalization.•The increase in ROS production associated with cell passage in MEFs is exacerbated in PGC-1α−/- MEFs.•PGC-1α−/- MEFs accumulate with cell passage higher levels of oxidative DNA damage than PGC-1α−+/+ MEFs.•Serially passaged PGC-1α−/- MEFs show in early induction of senescence markers that is not associated with a corresponding reduction in cell proliferation rates.•PGC-1α−/- MEFs, when serially passaged, immortalize earlier than PGC-1α−+/+ MEFs.