The regulation of coenzyme q biosynthesis in eukaryotic cells: all that yeast can tell us

Abstract

Coenzyme Q (CoQ) is a mitochondrial lipid, which functions mainly as an electron carrier from complex I or II to complex III at the mitochondrial inner membrane, and also as antioxidant in cell membranes. CoQ is needed as electron acceptor in β-oxidation of fatty acids and pyridine nucleotide biosynthesis, and it is responsible for opening the mitochondrial permeability transition pore. The yeast model has been very useful to analyze the synthesis of CoQ, and therefore, most of the knowledge about its regulation was obtained from the Saccharomyces cerevisiae model. CoQ biosynthesis is regulated to support 2 processes: the bioenergetic metabolism and the antioxidant defense. Alterations of the carbon source in yeast, or in nutrient availability in yeasts or mammalian cells, upregulate genes encoding proteins involved in CoQ synthesis. Oxidative stress, generated by chemical or physical agents or by serum deprivation, modifies specifically the expression of some COQ genes by means of stress transcription factors such as Msn2/4p, Yap1p or Hsf1p. In general, the induction of COQ gene expression produced by metabolic changes or stress is modulated downstream by other regulatory mechanisms such as the protein import to mitochondria, the assembly of a multi-enzymatic complex composed by Coq proteins and also the existence of a phosphorylation cycle that regulates the last steps of CoQ biosynthesis. The CoQ biosynthetic complex assembly starts with the production of a nucleating lipid such as HHB by the action of the Coq2 protein. Then, the Coq4 protein recognizes the precursor HHB acting as the nucleus of the complex. The activity of Coq8p, probably as kinase, allows the formation of an initial pre-complex containing all Coq proteins with the exception of Coq7p. This pre-complex leads to the synthesis of 5-demethoxy-Q6 (DMQ6), the Coq7p substrate. When de novo CoQ biosynthesis is required, Coq7p becomes dephosphorylated by the action of Ptc7p increasing the synthesis rate of CoQ6. This critical model is needed for a better understanding of CoQ biosynthesis. Taking into account that patients with CoQ10 deficiency maintain to some extent the machinery to synthesize CoQ, new promising strategies for the treatment of CoQ10 deficiency will require a better understanding of the regulation of CoQ biosynthesis in the future.

Keywords: Coenzyme Q; Mitochondria; Protein complex; Respiration; Ubiquinone; Yeast.

Fig. 1

Biosynthetic pathway of CoQ in yeast. The pathway of CoQ₆ biosynthesis starting from the first molecule with the quinone structure (polar ring and isoprene chain). This molecule is produced by the action of Coq1p and Coq2p that are not included in the scheme. Coq6p is a monooxygenase that catalyzes the DHHB synthesis and probably the synthesis of 2-methoxy-6-hexaprenyl-1,4-benzoquinone; Coq3p is an O-methyltransferase that catalyzes 2 O-methylations, Coq5p catalyzes a C-methylation and Coq7p catalyzes the hydroxylation of DMQ₆. For the decarboxylation of 4-methoxy-3-hydroxy hexaprenyl benzoate, the responsible enzyme has not been found. Other proteins such as Coq4p and Coq8p are required to synthesize CoQ₆ but do not show catalytic activity.

Fig. 2

Summary of the transcriptional regulation of CoQ₆ biosynthesis depending on carbon sources and the bioenergetic metabolism. CoQ₆ biosynthesis is modulated by several transcription factors related to the response to different fermentable and non-fermentable carbon sources, and also by amino acid deprivation. Green factors indicate activation and red factors correspond to repression. Black numbers indicate documented expression and grey numbers correspond to a putative expression of the respective COQ genes and PTC7.

Fig. 3

Model of the biosynthetic complex for CoQ₆. The model is a summary of already published data and non-well-defined ideas shown in the text. A The precursor. The first quinone-like molecule is the 4-hydroxy-3-hexaprenyl benzoate (HHB) that is produced by the action of Coq1p and Coq2p in mitochondria. Both proteins are required to synthesize CoQ₆ but are not present in the complex. HHB is accumulated at the exponential phase of growth during fermentation. B The nucleation. Coq4p recognizes HHB and starts the nucleation process. The action of Coq4p must be triggered by the mere accumulation of Coq4p produced when cells reach the PDS. However, previous activation by a kinase cannot be excluded. C Formation of the 700-kDa pre-complex. During the PDS, the activity of Coq4p bound to HHB starts the recruitment of Coq proteins to produce the 700-kDa complex or pre-complex. D Pre-complex activity. Because the pre-complex does not contain Coq7p, the activity of the pre-complex facilitates the accumulation of DMQ₆ during PDS. E The role of Ptc7p on the final assembly. Coq7p has been phosphorylated previously and cannot be a component of the pre-complex due to steric hindrance or charge repulsion with some components of the pre-complex. The phosphatase Ptc7p dephosphorylates Coq7p, erasing the repulsion from the pre-complex. F The full complex assembly. Coq7p bound to the pre-complex catalyzes the penultimate step of CoQ₆ biosynthesis after the formation of the full 1,300-kDa complex.