Absence of PGC-1α induces cellular senescence and early immortalization

Abstract

Peroxisome Proliferator Activated Receptor (PPAR) γ Coactivator 1α (PGC-1α) is a master regulator of oxidative metabolism; being responsible of the Reactive Oxygen Species (ROS) detoxification, and the lack of PGC-1α leads to oxidative stress due to ROS accumulation. It is well-known that elevated concentrations of ROS can cause Double Strand Breaks (DSB) in the DNA. Oxidative stress and DNA damage are, among others, triggers of Cellular Senescence, a cellular process characterized by cell cycle arrest in response of aberrant proliferation and tumor progression. The aim of the study was to determine the possible role of PGC-1α in cellular senescence. To test this idea, we used PGC-1a+/+ and PGC-1a-/- MEFs that were serially passed till they reach cellular senescence and immortalized spontaneously. Our results show that, in the absence of PGC-1a, MEFs produce higher levels of mitochondrial reactive oxygen species, accumulate more oxidative DNA damage measured by DNA damage repair complexes formation and showed delayed DNA repair, leading to an early induction of senescence markers and induction of cell cycle inhibitors. However, cell proliferation rate was not significantly different between PGC-1a+/+ and PGC-1a-/- MEFs regardless of passage number. Importantly, PGC-1a-/- MEFs showed and early escape from senescence, compared to PGC-1a+/+ MEFs. These results suggest that the lack of PGC-1α leads to enhanced DNA damage and induction of senescence, but is also associated with an early escape from cellular senescence, supporting a tumor suppressor role for PGC-1α.