Coenzyme Q supplementation or over-expression of the yeast Coq8 putative kinase stabilizes multi-subunit Coq polypeptide complexes in yeast coq null mutants

Abstract

Coenzyme Q biosynthesis in yeast requires a multi-subunit Coq polypeptide complex. Deletion of any one of the COQ genes leads to respiratory deficiency and decreased levels of the Coq4, Coq6, Coq7, and Coq9 polypeptides, suggesting that their association in a high molecular mass complex is required for stability. Over-expression of the putative Coq8 kinase in certain coq null mutants restores steady-state levels of the sensitive Coq polypeptides and promotes the synthesis of late-stage Q-intermediates. Here we show that over-expression of Coq8 in yeast coq null mutants profoundly affects the association of several of the Coq polypeptides in high molecular mass complexes, as assayed by separation of digitonin extracts of mitochondria by two-dimensional blue-native/SDS PAGE. The Coq4 polypeptide persists at high molecular mass with over-expression of Coq8 in coq3, coq5, coq6, coq7, coq9, and coq10 mutants, indicating that Coq4 is a central organizer of the Coq complex. Supplementation with exogenous Q6 increased the steady-state levels of Coq4, Coq7, Coq9, and several other mitochondrial polypeptides in select coq null mutants, and also promoted the formation of late-stage Q-intermediates. Q supplementation may stabilize this complex by interacting with one or more of the Coq polypeptides. The stabilizing effects of exogenously added Q6 or over-expression of Coq8 depend on Coq1 and Coq2 production of a polyisoprenyl intermediate. Based on the observed interdependence of the Coq polypeptides, the effect of exogenous Q6, and the requirement for an endogenously produced polyisoprenyl intermediate, we propose a new model for the Q-biosynthetic complex, termed the CoQ-synthome.

Secondary coenzyme Q 10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders

“…Moreover, since the enzymes involved in CoQ synthesis may exist in a super-enzyme complex closely linked to the respiratory chain in the inner mitochondrial membrane (studies in yeast), if the respiratory chain is not fully expressed or abnormal then this may cause a defect in the structural formation of the CoQ super-enzyme complex resulting in an abnormality in CoQ biosynthesis (He et al, 2014). and NDUFS4, which is a MRC complex I subunit defect.…”

Biosynthesis of coenzyme Q in eukaryotes

“…The level of CoQ10 differs between patients and depends on the specific mutations, and some Notes: The enzymes involved in CoQ synthesis form a complex in S. cerevisiae. 78) There is also some evidence that this complex exists in humans. This figure is modified from the figure reported by Allan et al 72) Proteins in the figure are not proportional to the actual molecular sizes.…”

“…Coq9 associates weakly with the complex, and Coq2 and Coq8 function separately. 78) Coq8 is a kinase that is involved in complex formation through the phosphorylation of Coq3, Coq5, and Coq7; however, it is unclear whether Coq8 phosphorylates these proteins directly or indirectly. Several lines of evidence indicate that the human CoQ biosynthetic enzymes also form a complex; 66,79) this topic has been comprehensively reviewed by Gonzalez-Mariscal et al 80) …”

CoQ10 Function and Role in Heart Failure and Ischemic Heart Disease

“…CoQ and its precursor, demethoxy-Q, stabilize this complex and thereby facilitate CoQ synthesis (181). Similarly, the maintenance or assembly of the CoQ synthome is affected by phosphorylation (69). There is also evidence that, in mice, two nuclear receptors, retinoid X receptor alpha (RXRα) and liver X receptor alpha (LXR-α), influence CoQ synthesis (13), although regulatory mechanisms that increase or repress CoQ biosynthesis are not well understood, especially under stress or disease states.…”