Coenzyme Q10 deficiencies: pathways in yeast and humans

Abstract

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1–COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1–COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway.

The kynurenine pathway is essential for rhodoquinone biosynthesis in Caenorhabditis elegans

“…Our study reveals that from the kynurenine pathway branch point, Q and RQ biosynthesis in C. elegans make use of common enzymes, since coq-5 and coq-6 RNAi led to a significant decrease of both quinones. The fact that the enzymes involved in Q biosynthesis do not have strict substrate specificity is highlighted by the parallel pathways of Q biosynthesis in yeast that start from different precursors (23). In addition, neo-functionalization of Coq enzymes has been described for the COQ-5 bacterial ortholog (UbiE/MenG) in the biosynthesis of menaquinone (28).…”

Strategies for fighting mitochondrial diseases

“…These water‐soluble CoQ head precursors would bypass enzymatic steps disrupted by mutations in COQ genes, but their efficacy may differ depending on the stability of the CoQ biosynthetic complex. Recent examples are vanillic acid (VA) and 3,4‐dihydroxybenzoate (3,4‐dHB), which are able to bypass COQ6 and COQ9 mutations [96], or 2,4‐dHB for COQ7 defects [97]).…”

COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10

“…Attempts to ameliorate the consequences of primary Q 10 deficiency by early Q 10 supplementation have been partially successful in some cases (8); however, many patients fail to demonstrate full recovery, which is related to inefficient uptake of orally supplied Q 10 . Due to the striking homology between human COQ genes and those of Saccharomyces cerevisiae (7,9), studies of Q 6 biosynthesis in S. cerevisiae may provide insight into human Q 10 biosynthesis, leading to the discovery of potential therapeutic targets.…”

“…In S. cerevisiae, at least fourteen nuclear encoded mitochondrial proteins (Coq1-Coq11, Yah1, Arh1, and Hfd1) drive Q 6 biosynthesis (7,9). Many Coq polypeptides (Coq3-Coq9, and Coq11) are localized to the matrix side of the mitochondrial inner membrane, where they organize into a high molecular weight, multisubunitcomplex known as the 'CoQ synthome' (7,9). Several lines of evidence suggest that correct assembly of the CoQ synthome is necessary for efficient Q 6 biosynthesis (9)(10)(11)(12).…”

“…Many Coq polypeptides (Coq3-Coq9, and Coq11) are localized to the matrix side of the mitochondrial inner membrane, where they organize into a high molecular weight, multisubunitcomplex known as the 'CoQ synthome' (7,9). Several lines of evidence suggest that correct assembly of the CoQ synthome is necessary for efficient Q 6 biosynthesis (9)(10)(11)(12). In fact, deletion of certain COQ genes results in decreased levels of other Coq polypeptides and contributes to a destabilized CoQ synthome in these mutants (12,13).…”