Oncogene-induced senescence: Role of mitochondrial dysfunction

Abstract

Mitochondrial biogenesis is activated in response to different signals and environmental stimuli. Recent data demonstrate an important role for mitochondrial biogenesis in the development of cellular senescence. Normal cellular response to increased energy demand after oncogene stimulation includes the induction of mitochondrial respiration. However, strong and prolonged activation of oxidative phosphorylation leads to oxidative stress, nuclear and mitochondrial DNA damage, mitochondrial dysfunction and senescence. Mutations in tumor suppressors in cooperation with activated oncogenes trigger the shift from mitochondrial respiration to aerobic glycolysis supplying the cells with ATP and metabolic substrates. It has been shown that the reverse shift has antiproliferative effect on cancer cells. As in normal proliferating cells mtDNA concentration is proportional to the oxidative capacity of the cell, the antitumor therapy can be based on the stimulation of mtDNA replication. It is expected that such therapy will stimulate mitochondrial respiration and additional disruption of oxidative phosphorylation will produce more free radicals, DNA damage response and senescence.