Coenzyme Q – Biosynthesis and functions

https://doi.org/10.1016/j.bbrc.2010.02.147Get rights and content

Abstract

In addition to its role as a component of the mitochondrial respiratory chain and our only lipid-soluble antioxidant synthesized endogenously, in recent years coenzyme Q (CoQ) has been found to have an increasing number of other important functions required for normal metabolic processes. A number of genetic mutations that reduce CoQ biosynthesis are associated with serious functional disturbances that can be eliminated by dietary administration of this lipid, making CoQ deficiencies the only mitochondrial diseases which can be successfully treated at present. In connection with certain other diseases associated with excessive oxidative stress, the level of CoQ is elevated as a protective response. Aging, certain experimental conditions and several human diseases reduce this level, resulting in serious metabolic disturbances. Since dietary uptake of this lipid is limited, up-regulation of its biosynthetic pathway is of considerable clinical interest. One approach for this purpose is administration of epoxidated all-trans polyisoprenoids, which enhance both CoQ biosynthesis and levels in experimental systems.

Introduction

Coenzyme Q (CoQ) is present in every membrane of all cells in the body [1]. Under normal physiological conditions all cells biosynthesize functionally sufficient amounts of this lipid. Thus, in contrast to cholesterol, no redistribution via or uptake from the circulation is required. The liver does release a certain amount of newly synthesized CoQ that associates with VLDL and provides circulating lipoproteins with an antioxidant defense, but this pool is not redistributed to other organs. Consequently, measurement of blood levels of CoQ provides only limited information concerning its actual levels in organs and cells. Under various conditions attenuated synthesis results in reductions in these levels and disturbance of normal functions. Since dietary uptake of CoQ is limited to only a few percent, numerous efforts are continuously directed towards the preparations of forms that are taken up more efficiently or substitutes with functional properties similar to those of CoQ and which are taken up into the circulation and cells more extensively.

Section snippets

Functions of CoQ

Following its isolation and characterization in 1955, CoQ was originally shown to be a necessary component of the mitochondrial respiratory chain two years later. It functions as an electron carrier from complex I and II to complex III and, according to Mitchell’s protonmotive Q cycle, production of ubisemiquinone accounts for the energy conservation occurring at coupling site 2 of the respiratory chain [2].

Today, several other important functions are also associated with this lipid.

  • 1.

    The plasma

The mevalonate pathway

Starting from acetyl-CoA, the series of reactions that comprise the mevalonate pathway produces farnesyl-PP, the precursor for cholesterol, CoQ, dolichol and isoprenylated proteins [12] (Fig. 1). In addition, the intermediary isopentenyl-PP is utilized for the synthesis of dolichol and the isoprenoid side-chain of CoQ. Since the initial sequence of reactions leading to all end-products of the mevalonate pathway is identical, it might be expected that synthesis of these various lipids is

Up-regulation of CoQ synthesis

In the case of most metabolic pathways a large number of endogenous metabolites play regulatory rolls. Likewise, production of cholesterol, the main product of the mevalonate pathway, is regulated by several different substances, including oxysterols, squalene oxide, farnesol and its derivatives, geranylgeraniol and prenyl phosphates. It thus seems likely that endogenous compounds also regulate the biosynthesis of CoQ.

In HepG2 cells epoxidated derivatives of certain all-trans polyisoprenoids,

Deficiencies in CoQ synthesis

Some cases of CoQ deficiency in humans result from inactivating mutations in the genes encoding the relevant biosynthetic proteins. Depending on the localization and extent of the defect, the clinical symptoms vary greatly. The brain, cerebellum, muscles and/or kidney may be involved, usually resulting in complex disease patterns [22].

A number of the mutations are characterized, referred to as primary types, directly affect the proteins involved in the biosynthesis of the CoQ [23] (Table 1).

Regulation of tissue levels of CoQ

The actual level of CoQ is determined by a coordinated balance between the synthetic and catabolic enzymes, which are both expressed in all tissues. This lipid is rapidly broken down, as reflected in its short half-life, T1/2, of 49–125 h in various tissues and the initial steps in this degradation involve ω-oxidation and subsequent β-oxidation of the side-chain [25]. The primary breakdown product detected in tissues, the urine and feces contains an intact, fully substituted ring, a short

Acknowledgments

The authors’ research is supported financially by the Family Erling-Persson Foundation and the Swedish Research Council.

References (36)

Cited by (363)

View all citing articles on Scopus
View full text