ИСТИНА

The mitochondrion is the major power station of the cell that generates most of the cell’s supply of ATP. The molecular mechanism of mitochondrial energy transformation involves the electron transport chain (ETC) that consists of electron transfer complexes I-IV embedded in the inner mitochondrial membrane. The ETC converts high energy potential of electrons from NADH and FADH2 into the energy of electrochemical proton gradient across the inner membrane that drives the synthesis of ATP by the ATP-synthase (complex V). Besides, mitochondria participate in the synthesis of many metabolic intermediates, including the de novo biosynthesis of pyrimidines. The latter process is catalyzed by dihydroorotate dehydrogenase (DHODH), an FMN flavoprotein in the inner mitochondrial membrane, which transfers electrons from dihydroorotate to ubiquinone of the ETC for further oxidation. The p53 tumor suppressor mediates important quality control functions by limiting proliferation and survival of abnormal or damaged cells. To the date there is little information regarding signals emitted by mitochondria that trigger p53 response. In our study we blocked by specific inhibitors each of the mitochondrial ETC complexes and monitored p53 induction. We conclude that neither the compounds that reduce MMP nor the suppression of ETC activity per se can trigger the p53 response. However, an activation of p53 and an induction of a p53-dependent apoptosis can be elicited specifically by inhibitors of mitochondrial complex III, which cause depletion of pyrimidines through the inhibition of a functionally coupled DHODH. We found that the deficiency in pyrimidines is critical for the induction of p53 in response to ETC complex III inhibitors. The results provide a previously unknown functional link between mitochondrial respiration and the p53 pathway.