RNA-binding proteins regulate cell respiration and coenzyme Q biosynthesis by post-transcriptional regulation of COQ7.

Abstract

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain carrying electrons from complexes I and II to complex III and it is an intrinsic component of the respirasome. CoQ concentration is highly regulated in cells in order to adapt the metabolism of the cell to challenges of nutrient availability and stress stimuli. At least 10 proteins have been shown to be required for CoQ biosynthesis in a multi-peptide complex and COQ7 is a central regulatory factor of this pathway. We found that the first 765 bp of the 3'-untranslated region (UTR) of COQ7 mRNA contains cis-acting elements of interaction with RNA-binding proteins (RBPs) HuR and hnRNP C1/C2. Binding of hnRNP C1/C2 to COQ7 mRNA was found to require the presence of HuR, and hnRNP C1/C2 silencing appeared to stabilize COQ7 mRNA modestly. By contrast, lowering HuR levels by silencing or depriving cells of serum destabilized and reduced the half-life of COQ7 mRNA, thereby reducing COQ7 protein and CoQ biosynthesis rate. Accordingly, HuR knockdown decreased oxygen consumption rate and mitochondrial production of ATP, and increased lactate levels. Taken together, our results indicate that a reduction in COQ7 mRNA levels by HuR depletion causes mitochondrial dysfunction and a switch toward an enhanced aerobic glycolysis, the characteristic phenotype exhibited by primary deficiency of CoQ10. Thus HuR contributes to efficient oxidative phosphorylation by regulating of CoQ10 biosynthesis.

• Authors: María V Cascajo, Kotb Abdelmohsen, Ji Heon Noh, Daniel J M Fernández-Ayala, Imke M Willers, Gloria Brea, Guillermo López-Lluch, Marina Valenzuela-Villatoro, José M Cuezva, Myriam Gorospe, Emilio Siendones, Plácido Navas
• Journal: RNA biology (RNA Biol) Vol. 13 Issue 7 Pg. 622-34 (07 02 2016) ISSN: 1555-8584 [Electronic] United States
• PMID: 26690054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural)

Chemical References

• 3' Untranslated Regions
• ELAV-Like Protein 1
• ELAVL1 protein, human
• Heterogeneous-Nuclear Ribonucleoprotein Group C
• Ubiquinone
• ubiquinone 7

Topics

• 3' Untranslated Regions (physiology)
• ELAV-Like Protein 1 (genetics, metabolism)
• Gene Expression Regulation (physiology)
• HeLa Cells
• Heterogeneous-Nuclear Ribonucleoprotein Group C (genetics, metabolism)
• Humans
• Oxidative Phosphorylation
• Oxygen Consumption (physiology)
• Ubiquinone (biosynthesis, genetics)