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Pyrimidine Biosynthesis Links Mitochondrial Respiration to the P53 Pathway

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Pyrimidine Biosynthesis Links Mitochondrial Respiration to the P53 Pathway Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway Anastasia A. Khutornenkoa, Vladimir V. Roudkoa, Boris V. Chernyaka,b, Andrey B. Vartapetiana, Peter M. Chumakovc,d,1, and Alexandra G. Evstafievaa,b,1 aBelozersky Institute of Physico-Chemical Biology, Moscow State University, 119992, Moscow, Russia; bInstitute of Mitoengineering, Moscow State University, 119992, Moscow, Russia; cLerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; and dEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Street 32, Moscow 119991, Russia Edited* by George R. Stark, Lerner Research Institute NE2, Cleveland, OH, and approved May 18, 2010 (received for review September 25, 2009) While many functions of the p53 tumor suppressor affect mito- stimulates mitochondrial respiration and ATP production chondrial processes, the role of altered mitochondrial physiology through up-regulation of SCO2 and AIF genes (7, 8). in a modulation of p53 response remains unclear. As mitochondrial Despite the established significance of p53 in mitochondrial respiration is affected in many pathologic conditions such as hyp- physiology there is little information regarding signals emitted oxia and intoxications, the impaired electron transport chain could by mitochondria that trigger p53 response. Yet substantial emit additional p53-inducing signals and thereby contribute to changes in mitochondrial respiration and in the activity of ETC tissue damage. Here we show that a shutdown of mitochondrial are observed during exposure to hypoxia (9) as the side effects of respiration per se does not trigger p53 response, because inhibitors drugs leading to hepatotoxicity (10) and cardiotoxicity (11) in the acting in the proximal and distal segments of the respiratory chain inherited succinate dehydrogenase deficiency associated with the do not activate p53. However, strong p53 response is induced spe- development of paragangliomas and pheochromocytomas (12), cifically after an inhibition of the mitochondrial cytochrome bc1 etc. Activation of p53 in response to an obstruction of mitochon- (the electron transport chain complex III). The p53 response is trig- drial ETC may additionally contribute to tissue damage. Mito- gered by the deficiency in pyrimidines that is developed due to a chondrial ROS were implicated in uncoupling of ETC and in suppression of the functionally coupled mitochondrial pyrimidine p53 activation in response to hypoxia (13). However, the role biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In of mitochondrial ETC activity in the induction of p53 response BIOCHEMISTRY epithelial carcinoma cells the activation of p53 in response to remains ambiguous. It was suggested that mitochondrial activity mitochondrial electron transport chain complex III inhibitors does could be required for the stress-induced activation of p53, as in- not require phosphorylation of p53 at Serine 15 or up-regulation of hibitors of complexes I and V mitigate the response to etoposide p14ARF. Instead, our data suggest a contribution of NQO1 and treatment (14) and inhibitors of complex III interfere with the NQO2 in stabilization of p53 in the nuclei. The results establish activation of p53 after treatment with cisplatin (15). On the other the deficiency in pyrimidine biosynthesis as the cause of p53 hand, it was noticed that certain ETC inhibitors produce a cell response in the cells with impaired mitochondrial respiration. senescence phenotype associated with a modest activation of p53, leading to the suggestion that the reduced mitochondrial dihydroorotate dehydrogenase ∣ mitochondrial electron transport chain ∣ membrane potential (MMP) could initiate the p53 response (16). NQO1 and NQO2 ∣ p53 tumor suppressor ∣ apoptosis In this study we blocked by specific inhibitors each of the mi- tochondrial ETC complexes and monitored p53 induction. We he mitochondrion is the major power station of the cell that conclude that neither the compounds that reduce MMP nor the Tgenerates most of the cell’s supply of ATP. In addition, mito- suppression of ETC activity per se can trigger the p53 response. chondria are involved in a range of intracellular processes, such However, an activation of p53 and an induction of a p53-depen- as cell growth and division, differentiation, apoptosis, and intra- dent apoptosis can be elicited specifically by inhibitors of mito- cellular signaling (1). The molecular mechanism of mitochondrial chondrial complex III, which cause depletion of pyrimidines energy transformation involves the electron transport chain through the inhibition of a functionally coupled DHODH. We (ETC) that consists of electron transfer complexes I-IV em- found that the deficiency in pyrimidines is critical for the induc- bedded in the inner mitochondrial membrane. The ETC converts tion of p53 in response to ETC complex III inhibitors. The results high energy potential of electrons from NADH and FADH2 into provide a previously unknown functional link between mitochon- the energy of electrochemical proton gradient across the inner drial respiration and the p53 pathway and suggest a contribution membrane that drives the synthesis of ATP by the ATP-synthase of NQO1 and NQO2 in stabilization and nuclear retention of p53 (complex V). Besides, mitochondria participate in the synthesis in epithelial cells with exhausted pools of pyrimidine nucleotides. of many metabolic intermediates, including the de novo biosyn- thesis of pyrimidines. The latter process is catalyzed by dihydro- Results orotate dehydrogenase (DHODH), an FMN flavoprotein in ETC Complex III Inhibitors Specifically Up-Regulate p53 and Induce a the inner mitochondrial membrane, which transfers electrons p53-Dependent Apoptosis. To find whether the deficiency in mito- from dihydroorotate to ubiquinone of the ETC for further chondrial respiration can elicit p53 response we studied the oxidation (2). accumulation of p53 in cells treated with inhibitors of different The p53 tumor suppressor mediates important quality control functions by limiting proliferation and survival of abnormal or Author contributions: B.V.C., P.M.C., and A.G.E. designed research; A.A.K., V.V.R., P.M.C., damaged cells. Mitochondria are critically important for the and A.G.E. performed research; B.V.C., A.B.V., P.M.C., and A.G.E. analyzed data; and P.M.C. p53-mediated cell death, because p53 controls transcription of and A.G.E. wrote the paper. several genes that affect the release of mitochondrial cytochrome The authors declare no conflict of interest. c (3). In addition, p53 can induce a transcription-independent *This Direct Submission article had a prearranged editor. apoptosis through the direct interaction with Bcl-2 family pro- 1To whom correspondence may be addressed. E-mail: [email protected] or evstaf@ teins (4). On the other hand, p53 also plays homeostatic roles genebee.msu.ru. in mitochondria (5) as it controls mtDNA copy number through This article contains supporting information online at www.pnas.org/lookup/suppl/ the p53 regulated M2 subunit of ribonucleotide reductase (6) and doi:10.1073/pnas.0910885107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0910885107 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 30, 2021 mitochondrial ETC complexes. In RKO cells the treatment for cells we observed an induction of transcripts from the CDKN1A 16–18 h with complex I inhibitors piericidin and rotenone, com- (p21) gene (Fig. S3H) and accumulation of the p21 and Mdm2 plex II inhibitor TTFA, and cytochrome c oxidase (complex IV) proteins (Fig. S3I). Similarly, the induction of p21 was observed inhibitor KCN produced almost no effect on the level of p53. in A549 and HCT116 cells. However, a significant accumulation of p53 was observed after The myxothiazol treatment induced morphological changes the treatment with complex III inhibitors myxothiazol, stigmatel- characteristic to apoptotic cell death, which came along with lin, and antimycin A (Fig. 1A). Similar effects were observed in the increase in the fraction of Annexin V-positive cells (Fig. S4) A549 and HCT116 cells (Fig. S1 A and B). In HeLa cells there and processing of the effector caspases 3 and 7 (Fig. 1 D and E). was also a substantial up-regulation of p53 level in response to The changes were blocked when the myxothiazol treatment was myxothiazol and stigmatellin but no effect of piericidin and rote- carried out in the presence of the caspase inhibitor ZVAD-FMK B none (Fig. 1 ). A p53-dependent reporter was also markedly in- (Fig. 1 D and E and Fig. S4) and were substantially suppressed in – duced: 7 8-fold after the treatment with myxothiazol and the p53 knockout HCT116 cells (Fig. 1E and Fig. S4). stigmatellin and 2.5-fold after the treatment with antimycin A C (Fig. 1 ), while there was no effect of the inhibitors in the cells The p53 Up-Regulation Induced by Complex III Inhibitors Is Largely transfected with the control reporter plasmid containing antiox- D ROS- and MMP-Independent. Inhibition of complex III by myxothia- idant response elements (ARE) (Fig. S1 ). There was no activa- zol was previously shown to be associated with increased intracel- tion of the p53-dependent reporter after treatment with the lular levels of ROS (17). Correspondingly, we found a slightly inhibitors of complex I (piericidin), complex II (TTFA) and com- increased level of ROS in the cells treated with complex III in- plex IV (KCN or NaN3) (Fig. 1C and Fig. S1C). Similar results hibitors. The effects were sensitive to the ROS scavenger N-acet- were obtained with the RKO reporter cells, although the magni- ylcysteine (NAC) (Fig. S5 A and B). However, pretreatment of tude of the induction was less explicit due to higher background E RKO and A549 cells with NAC did not prevent the accumulation level (Fig. S1 ). We conclude that the induction of p53 response A is specifically triggered by the inhibition of ETC at complex III of p53 in response to complex III inhibitors (Fig. 2 and Fig. S6A), whereas it completely prevented the accumulation but not by the impairment of the ETC itself. B Myxothiazol that demonstrated the most pronounced effect of p53 in response to hydrogen peroxide (Fig.
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