Elsevier

Mitochondrion

Volume 4, Issues 5–6, September 2004, Pages 779-789
Mitochondrion

Cellular redox poise modulation; the role of coenzyme Q10, gene and metabolic regulation

https://doi.org/10.1016/j.mito.2004.07.035Get rights and content

Abstract

In this communication, the concept is developed that coenzyme Q10 has a toti-potent role in the regulation of cellular metabolism. The redox function of coenzyme Q10 leads to a number of outcomes with major impacts on sub-cellular metabolism and gene regulation. Coenzyme Q10's regulatory activities are achieved in part, through the agency of its localization in the various sub-cellular membrane compartments. Its fluctuating redox poise within these membranes reflects the cell's metabolic micro-environments. As an integral part of this process, H2O2 is generated as a product of the normal electron transport systems to function as a mitogenic second messenger informing the nuclear and mitochondrial (chloroplast) genomes on a real-time basis of the status of the sub-cellular metabolic micro-environments and the needs of that cell. Coenzyme Q10 plays a major role both in energy conservation, and energy dissipation as a component of the uncoupler protein family. Coenzyme Q10 is both an anti-oxidant and a pro-oxidant and of the two the latter is proposed as its more important cellular function. Coenzyme Q10 has been reported, to be of therapeutic benefit in the treatment of a wide range of age related degenerative systemic diseases and mitochondrial disease. Our over-arching hypotheses on the central role played by coenzyme Q10 in redox poise changes, the generation of H2O2, consequent gene regulation and metabolic flux control may account for the wide ranging therapeutic benefits attributed to coenzyme Q10.

Introduction

Some years ago, we proposed that mitochondrial DNA mutations are important contributors to the ageing process and degenerative diseases (Linnane et al., 1989). Further, that such conditions could be ameliorated by redox compounds, notably coenzyme Q10, acting to re-energize tissues and as an anti-oxidant. The basic tenets of the hypothesis have since been confirmed by our laboratory and many others [for review, Linnane, 2000, Kopsidas et al., 2000].

The purpose of this short essay, is to continue to extend and make some modifications to the original hypothesis with the proposal that coenzyme Q10 plays a totipotent role in the regulation of sub-cellular metabolism. Our hypothesis integrates several known and new aspects of coenzyme Q10 molecular biology to provide a basis upon which the multitude of its claimed biological/clinical effects may be considered. Coenzyme Q10 is known to occur in all sub-cellular membranes and has a functional role in many known membrane oxido-reductase systems therein; mitochondria, lysosomes, plasmalemma, Golgi apparatus. We propose that, in essence, it is coenzyme Q10's particular sub-cellular redox poise (ratio of reduced to oxidized form) changes that determines its key metabolic control function. The redox poise of coenzyme Q10 in the various membranes, will fluctuate continuously as an expression of the metabolic processes being carried out at any given time, within the various sub-cellular compartments, to produce a particular localized redox poise, resulting in a signaling process. This process together with coenzyme Q10 acting as a pro-oxidant will produce superoxide anion and the known mitogen H2O2; which then functions, as a second messenger to inform the nucleus, and mitochondria (chloroplasts) of the need for appropriate gene expression/regulation. The pro-oxidant role of coenzyme Q10 is envisaged as critical to healthy cell function. The biological role of coenzyme Q10 is thus complex; the effects of coenzyme Q10 administration and function will not be limited to a small number of pathways but influence the over-all metabolism of the cell through small localized sub-cellular metabolic perturbations. Coenzyme Q10 also plays a role in energy dissipation by the uncoupler proteins, both as a co-factor proton carrier and by the generation of superoxide, which activates the system. It can be readily envisioned that coenzyme Q10 will play an embracing role in modulating cellular well being and cellular pathology. Fig. 1 outlines the global functions of coenzyme Q10 in relation to sub-cellular bioenergy systems, redox poise, metabolic flux modulation, gene regulation and oxygen radical formation.

One of the main sources of evidence for our hypothesis is a human clinical trial we conducted investigating the effects of coenzyme Q10 on vastus lateralis muscle of aged (50–80 years) subjects scheduled to undergo hip replacement surgery (Linnane et al., 2002a, Linnane et al., 2002b). The human trial subjects received either 300 mg coenzyme Q10 or placebo per day for 25–30 days before surgery. At the time of surgery, a corresponding sample of the vastus lateralis muscle was taken for analysis from each of the subject cohorts. The impact of the coenzyme Q10 compared with placebo material on the molecular profile of the tissue, was surveyed using gene array and gene display technologies as well as protein expression patterns. In addition, the muscle tissue samples were assessed in regards to their muscle fibre type composition. It was appreciated that the analytical tools employed would yield results bearing only on a limited number of genes and proteins, but sufficient (several thousand) to answer the question as to whether coenzyme Q10 had a wide-ranging major effect on the muscle metabolic profile of aged subjects.

The gene expression profiles of human vastus lateralis samples taken from subjects receiving coenzyme Q10 or placebo were compared using Microarray and Differential Gene Display technologies. The overall results are summarized in Table 1 (data from Linnane et al., 2002a, Linnane et al., 2002b).

The Affymetrix U95A oligonucleotide array, which contains 12,000 annotated human genes, was used in the Microarray studies; many of the sequences belong to no known protein product. This survey showed that following 25–30 days of coenzyme Q10 administration, the change in expression of most detected transcripts compared to the placebo muscle samples were probably not significant. However, the expression of 115 gene transcripts underwent significant change (defined as up or down regulated by a factor of 1.8), compared to the placebo; of these, 47 were up-regulated and 68 down-regulated. While many of the coenzyme Q10 regulated genes were of unknown function, they did include; Glutamate Receptor Protein (GluR5), Fibroblast growth factor receptor (N-SAM), Protein kinase C-epsilon, Guanylyl cyclase, TTF-1 interacting peptide 20 (TIP-20), TR3 orphan receptor and HZF Helicase, among others. A cursory analysis demonstrates that a wide range of cellular functions have been influenced by coenzyme Q10 administration; some direct, others presumably a reflection of an induced metabolic flux. Further detailed studies are required to identify the individual components of skeletal muscle affected by whole body administration of coenzyme Q10.. For the present, such studies will be limited by the lack of gene array chips, which constitute a complete skeletal muscle gene atlas. However, our hypothesis at this time, only requires a demonstration of a global effect of coenzyme Q10 on tissue metabolism, which our muscle results support.

Differential Gene Display analyses were directed towards investigating myosin heavy chain expression having regard to the well known age associated muscle fibre type compositional changes. The Myosin Heavy chain type IIa and IIb were both up-regulated consistent with the observed histochemical results (see later). In addition, in this limited focused study, the analyses revealed that 15 genes appeared to be strongly influenced by coenzyme Q10 administration (12 up-regulated and 3 down-regulated); the expression of Adenylate cyclase 9, DNA ploymerase epsilon subunit, heat shock protein (HSP70) most notably, among others, were up-regulated, while the amounts of Telomerase, RNA I helicase and Glial fibrillary acidic protein were down-regulated. The Differential Gene Display result complemented the Microarray study in that both indicated that a complex mix of cellular functions appear to share an element of coenzyme Q10 regulation.

Microarrays containing the complete human genome are unavailable and more particularly skeletal muscle gene atlases do not exist at this time. Gene expression results are less informative relative to cellular protein compositional profiles which more directly reflect the cell's metabolic state. Furthermore, proteins are subject to post-transcriptional mechanisms that regulate their functional half-life and synthesis (Varshavsky, 1996) which can lead to a non-linear relationship between mRNA and protein levels, which brings into question the current value of gene array analyses, as a reflection of intermediary metabolism activity. Thus, invariant steady-state levels of some cellular proteins have been observed while their respective mRNA transcript levels varied by as much as 30-fold (Gygi et al., 1999).

The muscle proteome analyses of placebo and coenzyme Q10 samples were compared to determine coenzyme Q10 regulated proteins; about 2000–2200 high abundance proteins can be visualized by two-dimensional PAGE analyses. The vastus lateralis muscle protein profile of the placebo versus coenzyme Q10 treated subjects were clearly very different; 229 protein spots were up-regulated (induced) and 236 were repressed (decreased) in the muscle protein samples from coenzyme Q10 treated subjects compared with the placebos (Table 1). As would be expected, the majority of proteins in the samples were unaffected or little changed. While these analyses deal only with high expression proteins of the muscle (an additional 4–6000 probably make up the total muscle proteome), nonetheless a major impact is made by coenzyme Q10 on the metabolic profile of human vastus lateralis muscle of aged subjects. Maldi-TOF mass spectrometer technology could be used to characterize the different proteins modulated by coenzyme Q10 action.

It is well known that with increasing age, there is a change in the fibre type composition of skeletal muscle. In particular, the percentage of fast-twich fibres (Type II fibres) decrease relative to the slow twitch Type I fibres. The preferred energy systems of the three main muscle fibre types are; Type 1 mitochondrial, Type IIa balance between mitochondrial and glycolytic activity, and Type IIb obtain their energy mainly by glycolysis. The histochemical analyses data summarized in Fig. 2 (Linnane et al., 2002a, Linnane et al., 2002b) illustrate the effect of coenzyme Q10 administration to subjects on their muscle. Most strikingly, coenzyme Q10 appears to induce a change towards a younger muscle fibre composition profile. An increase in the percentage of fast twitch type II fibres relative to type I fibres was observed. Muscle weakness is a major feature of the aging process resulting in a decrease in mobility and loss of coordination, which impinges greatly on the elderly population. Coenzyme Q10 administration has a profound effect on human vastus lateralis skeletal muscle as demonstrated by its effect on gene activity, proteome changes and most significantly, on alteration in the physiological function of the muscle, albeit inferred from muscle fibre myosin type changes. Redox therapy by coenzyme Q10 in ameliorating muscle weakness could make a meaningful contribution to the improvement in the quality of life of the aged.

Section snippets

Cellular functions of coenzyme Q10

The diversity of cellular functions which significantly involve coenzyme Q10 are summarized in Table 2, and discussed below.

A clinical role for coenzyme Q10

It was not for about some 20 years after its discovery that a possible role for coenzyme Q10 as a therapeutic substance, began to emerge; many of the claims and assertions have recently been comprehensively reviewed (Ebadi et al., 2001). However, even to the present time, most of the therapeutic benefits claimed are essentially anecdotal and have accordingly not been accepted by the wider medical community. A selection of some of the wide-ranging claims for a beneficial clinical effect

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