Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway — PNAS

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
+ Author Affiliations

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)

Abstract
While many functions of the p53 tumor suppressor affect mitochondrial processes, the role of altered mitochondrial physiology in a modulation of p53 response remains unclear. As mitochondrial respiration is affected in many pathologic conditions such as hypoxia and intoxications, the impaired electron transport chain could emit additional p53-inducing signals and thereby contribute to tissue damage. Here we show that a shutdown of mitochondrial respiration per se does not trigger p53 response, because inhibitors acting in the proximal and distal segments of the respiratory chain do not activate p53. However, strong p53 response is induced specifically after an inhibition of the mitochondrial cytochrome bc1 (the electron transport chain complex III). The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14ARF. Instead, our data suggest a contribution of NQO1 and NQO2 in stabilization of p53 in the nuclei. The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration.

dihydroorotate dehydrogenasemitochondrial electron transport chainNQO1 and NQO2p53 tumor suppressorapoptosis

Footnotes

1To whom correspondence may be addressed. E-mail: chumakp@ccf.org or evstaf@genebee.msu.ru.
Author contributions: B.V.C., P.M.C., and A.G.E. designed research; A.A.K., V.V.R., P.M.C., 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. and A.G.E. wrote the paper.
The authors declare no conflict of interest.
*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.0910885107/-/DCSupplemental.

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Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway — PNAS