Elsevier

Mitochondrion

Volume 7, Supplement, June 2007, Pages S51-S61
Mitochondrion

Coenzyme Q10 – Its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolome

https://doi.org/10.1016/j.mito.2007.03.005Get rights and content

Abstract

Coenzyme Q10 plays a central role in cellular bioenergy generation and its regulation. Closed membrane systems generate a proton motive force to create transient localized bio-capacitors; the captured energy is used for the synthesis of mitochondrial ATP but also for many other processes, such as metabolite translocations, nerve conduction and a host of other bioenergy requiring processes. Coenzyme Q10 plays a key role in many of these sub-cellular membrane energy generating systems. Integral to this phenomenon is the prooxidant role of coenzyme Q10 in generating the major superoxide anion/hydrogen peroxide second messenger system. This messenger system, largely but not exclusively, arises from coenzyme Q10 semiquinone function; it contributes to the regulation of sub-cellular redox potential levels; transcription/gene expression control; is essential for modulated protein turnover and activation; mediates hormone and growth factor extracellular signaling. The regulated prooxidant formation of the superoxide anion/H2O2 second messenger system is essential for the normal physiological function of the metabolome. The normally functioning metabolome is the expression of a finely tuned dynamic equilibrium comprised of thousands of anabolic and catabolic reactions and all cellular signaling systems must be finely regulated. There is still much to be learnt about the up/down regulation of the H2O2 messenger system. The concept that superoxide anion/H2O2 cause random macromolecular damage is rebutted. The administration of antioxidants to quench the inferred toxicity of these compounds as a therapy for age associated diseases is unsupported by extant mammalian clinical trials and should be subject to serious re-evaluation. The role of ascorbic acid as a beneficial hydrogen peroxide prodrug is discussed.

Introduction

This paper, in the main, focuses on the formation of superoxide anion and hydrogen peroxide and its role as a second messenger. The essential prooxidant role of coenzyme Q10 and other superoxide anion/H2O2 generating systems is discussed. We continue to elaborate the thesis that the concept that superoxide anion/H2O2 are toxic products which randomly damage macromolecules and must be quenched by interventionist antioxidant therapy is flawed. On the contrary, there is an essential physiological requirement for superoxide anion/H2O2 formation, with H2O2 acting as a major second messenger required for normal metabolome function.

There is nothing more critical for all anabolic and catabolic cellular functions than an adequate, constant supply of bioenergy. Coenzyme Q10 was shown by Crane et al. (1957), some 50 years ago to be a key component of the mitochondrial electron transport system. Soon after coenzyme Q10 or its analogues were shown to be ubiquitous essential members of the electron transport and oxidative energy generating systems of bacteria and eukaryotic cells. Mitchell’s (1974) revolutionary work concerning the mechanism of conservation of mitochondrial redox potential energy, overturning a 25 year phosphorylated intermediate hypothesis, owed much to his formulation of the Q cycle hypothesis (Mitchell, 1975). Essentially the Q cycle concept centred around mitochondrial proton motive force generated by vectorial separation of protons across impermeable biomembranes, with coenzyme Q10 playing a key role. It has been established that a wide range of biomembrane systems are energized via a redox process which create transient localized bio-capacitors, which are utilized by the metabolome (for review, Linnane et al., 2007b).

At about this time, Boveris, Chance and colleagues reported in a series of papers that the mitochondrial electron transport system through the agency of coenzyme Q10 semiquinone gave rise to high concentrations of superoxide anion, and in turn, hydrogen peroxide (for review Chance et al., 1979). It was calculated that 1–3% of inspired oxygen was converted to superoxide anion and in such amounts would be highly toxic to tissues. These reports appeared to support the free radical theory of aging first proposed by Harman (1956). A voluminous literature has arisen which has concentrated upon establishing the essential need for antioxidant systems to prevent random oxidative damage to cells and among other compounds, orally administered coenzyme Q10 functions as an antioxidant (Ebadi et al., 2001). A major problem with the concept of antioxidant therapy for the treatment of age associated systemic diseases is that there are no human clinical trials which support such a conclusion. By way of example, antioxidant therapy has been promoted for many years for the prevention and treatment of cancers, based on non-physiological in vitro studies (Ames et al., 1993). A wealth of data speaks to the contrary. Bjelakovic et al. (2004) have reported a meta-analysis of a series of antioxidant therapy studies (over 170,000 participants) and found no benefit for the treatment/prevention of gastrointestinal cancers or any effect on participant mortality. These studies included the administration of tocopherol, ascorbic acid, selenium and β-carotene in various combinations (for discussion, Linnane et al., 2007a, Linnane et al., 2007b). Similarly Miller et al. (2005) following meta analyses of 135,967 participants in vitamin E supplementation trials concluded that high doses of 400 IU/day may increase all cause mortality and should be avoided. It may be that any putative therapeutic antioxidant administered needs to be targeted specifically to appropriate sub-cellular sites and tissues/organs to have the desired effect of quenching over production of ROS, if it occurs. However, the current antioxidants do not appear to fit this situation. Recently Bailey et al. (2006) have reported that ascorbate promotes oxidative damage during surgical ischemia reperfusion.

In essence this short review considers two aspects of coenzyme Q10 functions, its role in energy generating mammalian oxido-reductase systems and simultaneously the prooxidant formation of small amounts of second messenger superoxide anion/H2O2. The formation of the prooxidant superoxide anion/H2O2 couple is so critical to overall metabolome function that it is also relevant to briefly consider its formation by non-coenzyme Q10-dependent systems.

In considering/reviewing the encompassing biological function of coenzyme Q10 and prooxidants the subject matter can only be dealt with in a reductionist manner in this limited review. We have attempted to integrate a large body of work and publications emanating from diverse fields and as such include only two over-riding rather complex cartoon summary figures, relying on the text for clarification. Elsewhere in a series of papers the data summarized herein has been elaborated in more detail, we refer the reader particularly to Linnane et al. (2007b) for a more extensive treatment.

Section snippets

The role of coenzyme Q10 and sub-cellular signaling

Coenzyme Q10 acting through formation of its semiquinone is a major source of cellular and mitochondrial superoxide anion and consequently H2O2 formation. It also has a major role in mitochondrial energy generation actively participating in the establishment of the mitochondrial membrane’s proton motive force (Δp = Δψ + ΔpH). Coenzyme Q10 occurs in most, if not all, cellular membranes and, it is again therein an important source of superoxide anion/H2O2, for example, the Golgi apparatus and

H2O2 plasma membrane signaling specificity

The fact that the same extracellular effectors, e.g., PDGF, can stimulate both the CNOX and Nox systems to produce second messenger H2O2 raises the major unresolved problem of localized specificity. Does PDGF exposure lead to simultaneous H2O2 production by both systems, or is there some steric properties inherent in the plasma membrane which confers some selective effector regulatory specificity, and/or are there specific carriers (e.g., proteins) which move the H2O2 through the cell to elicit

Macromolecule oxidative changes and signaling

There is a voluminous literature reporting on oxidative damage to cellular macromolecular components by random, unregulated oxidation to cause deleterious damage leading to macromolecular and cellular dysfunction, thereby contributing to the aging process and age associated diseases. The process involving oxidative modification of macromolecules is much more subtle in its out workings.

Oxidatively modified proteins and regulated protein turnover

Protein degradation is exquisitely regulated; many proteins have half lives of only a few hours or less while others survive for days and weeks; the temporal turnover of these proteins is part of cellular metabolic regulation. Early studies of cellular proteolysis systems were concerned with the cathepsins, a group of proteases with acidic optima of about pH5 encapsulated within lysosomes in order to protect the cell from random proteolytic action. The role of the cathepsins was supposedly to

Mitochondrial DNA

Age related decline in bioenergy capacity below a crucial threshold will obviously contribute to cellular malfunction. The development of mitochondrial tissue bioenergy mosaics with age, exemplified by null, low and normal cytochrome oxidase cell content has been stringently correlated at the single cell level, by our laboratory, with mtDNA deletions and the individual cell content of full-length functional mtDNA (Linnane et al., 1989, Nagley et al., 1993, Kovalenko et al., 1998, Kopsidas et

Redox regulation of cellular metabolism and differentiation

The early work of Smith et al. (2000) on rat glial oligodendrocytes progenitor cell differentiation teaches that cellular redox poise regulates the process. Oligodendrocyte/astrocyte progenitor cells can be grown under conditions to establish a more oxidizing redox cytoplasmic environment, such conditions favour cell differentiation to oligodendrocyte or astrocyte formation. By contrast, a more reducing redox cytoplasmic environment favoured the maintenance of the progenitor cells. A

The chimera of antioxidant (theory and) therapy?

The theme running through this short review is that a random antioxidant scavenging of superoxide anion (H2O2) would catastrophically derange their second messenger function which is essential for the regulation of major metabolome activities. The chimera of antioxidant therapy we have briefly considered elsewhere (Linnane and Eastwood, 2004). There is no compelling evidence from human clinical studies, conducted with sharp end points, to support the claims that the ingestion of small molecule

Ascorbic acid, a hydrogen peroxide prodrug

Vitamin C has long been promoted as an outstanding antioxidant and of benefit in the prevention/amelioration of age associated diseases proposedly arising from oxygen radical damage but it has yet to demonstrated that it has any role as a meaningful therapeutic antioxidant. However ascorbate has been promoted by some complementary medicine practitioners for the treatment of cancers but the data in support of an efficacious outcome is equivocal. The rationale for this therapy, has been the

The over arching role of coenzyme Q10 and hydrogen peroxide in the regulation of the metabolome and the disease process

The over arching normal physiological roles of coenzyme Q10 and superoxide anion/H2O2 are summarized in Figs. 1a and b and discussed throughout the text.

For over 20 years there have been numerous anecdotal reports of orally administered coenzyme Q10 acting beneficially in the treatment of a wide range of apparently unrelated diseases (Table 1). For most practitioners these claims have been greeted with scepticism and coenzyme Q10 has not been widely embraced as being therapeutically useful. One

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