Journal Article

Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway

Chernyak, Boris V., Evstafieva, Alexandra G., Roudko, Vladimir V., Vartapetian, Andrey B., Chumakov, Peter M., Khutornenko, Anastasia A., Stark, George R.

2010

Overview

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 p14 ARF . 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Actins / Apoptosis / Apoptosis - drug effects / Biological Sciences / Biosynthesis / Carcinoma / Cell Line, Tumor / Cell lines / Cell Respiration - drug effects / Cytochrome bc1 / Data processing / Dihydroorotate dehydrogenase / DNA damage / Electron transfer / Electron transport / Electron transport chain / Electron Transport Complex III - antagonists & inhibitors / Electron Transport Complex III - metabolism / Enzymes / Epithelial cells / epithelium / HCT116 cells / HeLa cells / Humans / Hypoxia / Intoxication / Isoxazoles - pharmacology / Membrane Potential, Mitochondrial - drug effects / Methacrylates - pharmacology / Mitochondria / Mitochondria - drug effects / Mitochondria - enzymology / Mitochondria - metabolism / NAD(P)H dehydrogenase (quinone) / NAD(P)H Dehydrogenase (Quinone) - metabolism / neoplasm cells / Nuclei / Organic chemicals / Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors / Oxidoreductases Acting on CH-CH Group Donors - deficiency / p14ARF protein / p53 protein / Phosphorylation / Potassium Cyanide - pharmacology / Proteasome Endopeptidase Complex - metabolism / Protein Processing, Post-Translational - drug effects / Pyrimidines / Pyrimidines - biosynthesis / Quinone Reductases - metabolism / Reactive Oxygen Species - metabolism / Respiration / Serine / Signal transduction / Signal Transduction - drug effects / Thiazoles - pharmacology / Tissues / Tumor suppressor genes / Tumor Suppressor Protein p53 - metabolism / Tumors / Up regulation / Up-Regulation - drug effects