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Khutornenko AA, Dalina AA, Chernyak BV, et al. The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. Acta Naturae. 2014;6(1):69-75
Khutornenko, A. A., Dalina, A. A., Chernyak, B. V., Chumakov, P. M., & Evstafieva, A. G. (2014). The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. Acta naturae, 6(1), 69-75.
Khutornenko, A A, et al. "The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III." Acta naturae vol. 6,1 (2014): 69-75.
Khutornenko AA, Dalina AA, Chernyak BV, Chumakov PM, Evstafieva AG. The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. Acta Naturae. 2014 Jan;6(1):69-75. PMID: 24772329; PMCID: PMC3999468.
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Acta Naturae. 2014 Jan;6(1):69-75.

The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III.

Acta naturae

A A Khutornenko, A A Dalina, B V Chernyak, P M Chumakov, A G Evstafieva

Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory, 1, Bld. 40, 119991, Moscow, Russia.
  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str., 32, 119991, Moscow, Russia.
  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory, 1, Bld. 40, 119991, Moscow, Russia ; Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskie Gory, 1, Bld. 73, 119991, Moscow, Russia.

PMID: 24772329 PMCID: PMC3999468

Abstract

A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death.

Keywords: apoptosis; de novo pyrimidine biosynthesis; dihydroorotate dehydrogenase; mitochondrial respiratory chain; p53 tumor suppressor

References

  1. J Intern Med. 2008 Feb;263(2):167-78 - PubMed
  2. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14775-80 - PubMed
  3. Apoptosis. 2012 Mar;17(3):258-68 - PubMed
  4. Mol Biol. 2006 May 1;40(3):396-405 - PubMed
  5. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12828-33 - PubMed
  6. Curr Biol. 2006 Jul 25;16(14):R551-60 - PubMed
  7. Nature. 2007 Mar 1;446(7131):88-91 - PubMed
  8. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6314-9 - PubMed
  9. Biochemistry (Mosc). 2007 Dec;72(13):1399-421 - PubMed
  10. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16278-83 - PubMed
  11. J Biol Chem. 2004 Aug 6;279(32):33035-8 - PubMed
  12. Neoplasia. 2010 Jun;12(6):464-75 - PubMed
  13. Mol Cancer Ther. 2009 Feb;8(2):366-75 - PubMed
  14. J Immunol Methods. 2002 Aug 1;266(1-2):185-96 - PubMed
  15. Biochim Biophys Acta. 2013 Nov-Dec;1827(11-12):1346-61 - PubMed

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