RNA-binding proteins regulate cell respiration and coenzyme Q biosynthesis by post-transcriptional regulation ofCOQ7

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 multipeptide complex and COQ7 is a central regulatory factor of this pathway. We found that the first 765 bp of the 3 0 -untranslated region (UTR) of COQ7 mRNA contains cis-acting elements of interaction with RNAbinding 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 CoQ 10 . Thus HuR contributes to efficient oxidative phosphorylation by regulating of CoQ 10 biosynthesis.

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

“…Thus, TIA1/TIAR and HuR could orchestrate biological responses and programs whose targets may be linked to mitochondrial activity and dynamics. Accordingly, two mitochondrial components linked to survival/cell death and/or electron transport chain, cytochrome c and coenzyme Q, are posttranscriptionally regulated by TIA1/TIAR and/or HuR (55,56).…”

Coenzyme Q10 Supplementation in Aging and Disease

“…The assembly and stabilization of the synthome is far from being understood as it may encompass yet to be discovered new interacting protein partners (Allan et al, 2015 ; Morgenstern et al, 2017 ). CoQ biosynthesis pathway is tightly regulated both at the transcriptional and translational levels (Turunen et al, 2000 ; Brea-Calvo et al, 2009 ; Cascajo et al, 2016 ) and by phosphorylation of some of the complex components (Martin-Montalvo et al, 2011 , 2013 ; Guo et al, 2017 ; He et al, 2017 ).…”

Biochemical Assessment of Coenzyme Q10 Deficiency

“…Another important approach to assess CoQ 10 deficiency in cells is to determine the rate of biosynthesis by the level of incorporation of labeled of CoQ 10 precursors such as para -hydroxybenzoate ( p -HB) labeled with either 13 C- p -HB or 14 C- p -HB, which is the precursor of the benzoquinone ring, or 2 H-mevalonate, which is the precursor of the isoprenyl side chain [10,60]. …”

“…Biosynthesis of 14 C-CoQ 10 has been quantified in any type of cell culture, such as cancer cells, human skin fibroblasts, and murine embryonic fibroblast and stem cells [10,61]. Previously, cultures were incubated with 4.5 nM 14 C- p- HB for one to three days, depending on the cell-specific rate of growth.…”

“…The CoQ 10 biosynthesis pathway is highly regulated by transcription factors PPARα and NFκB [7,8,9]. HuR and hnRNP C1/C2 binding proteins stabilize COQ7 mRNA as another CoQ 10 biosynthesis regulatory mechanism [10]. …”