The 5th Conference of the International Coenzyme Q10 Association took place in Kobe in November 9-12, 2007, two and half years after the previous Conference in Los Angeles. The Conference was organized by Dr. Takeo Kishi of the Kobe-Gakuin University, together with Dr. Gian Paolo Littarru, President of the Association and with the executive committee of the Association. The event coincided with the 50th anniversary of the discovery by Dr. Frederick Crane of Coenzyme Q as an obligatory electron carrier in mitochondria; for this reason the organizing committee decided to emphasize the basic bioenergetic and metabolic aspects of Coenzyme Q10. The meeting was memorable from both the stand-point of the organization and of the scientific contents: indeed in my opinion it was one of the best in the history of Coenzyme Q10 Symposia.
One general point which directly or indirectly emerged from the talks in the Meeting was the confirmation of a broad range of different functions of this molecule. Although not explicitly stated, a function of CoQ at the genetic transcriptional level may be inferred from the amazing results of some clinical investigations on the bioenergetic functions of the heart; paradigmatic are the studies of F. Rosenfeldt on preoperative treatment and of P. Langsjoen on congestive heart failure: rather than restoring compromised bioenergetics of pre-existing mitochondria, it is likely that Coenzyme Q10 acts at the genetic level by improving mitochondrial biogenesis. This is a testable hypothesis and should be pursued in the future.
The Conference opened with an introductory lecture by the discoverer of Coenzyme Q: Fred Crane provided a lucid historical overview of the different functions of the molecule with his usual authority and humility, emphasizing the possible future developments. After Crane’s talk, T. Ramasarma (Bangalore) added similar considerations, also pointing out how many catabolic derivatives of Coenzyme Q may have unknown important functions.
The sessions of the Conference were well balanced between different topics. The basic science sessions included Bioenergetics, Antioxidants aspects, Biosynthesis and metabolic aspects.
The first session very appropriately covered the bioenergetic aspects: it is surprising that years after the mitochondrial community believed there was nothing more to discover in the field of oxidative phosphorylation, so many novel findings have opened new routes for investigation.
Sergio Papa (Bari) reviewed the mechanisms of energy conservation in mitochondria by means of proton translocation: although proton translocation across the respiratory Complex III is recognized to take place by vectorial proton equilibria during redox reactions (the so-called “Q-cycle”), the mechanism by which protons are moved across Complex I is much less understood. Tomoko Ohnishi (Philadelphia), the main world expert of EPR in bioenergetics, addressed this very topic by analyzing the EPR signals of CoQ semiquinone and FeS clusters of Complex I: the properties of a CoQ semiquinone signal (CoQNf) appearing in coupled submitochondrial particles allow to propose a novel model of proton pump based on the equilibrium between two conformational states of the CoQNf-binding protein. Maria Luisa Genova (Bologna) then discussed the implications of a supercomplex organization of the respiratory chain, where the demonstrated structural and functional link between complexes I and III challenges the notion of a functional CoQ pool in the membrane; actually the pool is needed to shift the dissociation equilibrium of CoQ into the supercomplex. This understanding allows to explain the beneficial effect of excess exogenous CoQ on electron transfer. Paolo Bernardi (Padova) reviewed the effect of different quinones on the permeability transition pore of the mitochondrial membrane whose nature remains still elusive despite so many investigations. The importance of bacterial quinone enzymes in understanding mechanisms occurring in higher organisms were apparent in the lecture by Mamoru Yamada (Yamaguchi) on bound ubiquinone in E. coli glucose dehydrogenase.
The second session concerned the antioxidant properties of CoQ. The introductory lecture by Romana Fato (Bologna) demonstrated that the electron donor to oxygen in Complex I to generate superoxide is an iron sulphur cluster, thus excluding the CoQ10 semiquinone as prooxidant as suggested by several investigators, and allowing to propose a novel mechanism of electron transfer to the quinone acceptor. Isuke Imada (Osaka) reported the effect of short chain quinones including idebenone, a CoQ analogue widely employed in therapy, analyzing both their antioxidant role when reduced and their capability to generate ROS by interacting with oxygen. Two papers compared the antioxidant properties of ubiquinol and Vitamin E. Kazuo Mukai (Matsuyama) in a detailed kinetic study examined the reaction rate constants as antioxidants and the actual rates based on concentration, showing that in mitochondria of different tissues the actual rates are much higher for ubiquinol. Yoshiro Saito (AIST, Osaka) compared the two molecules on the basis of subcellular localization, showing that α-tocopherol is mainly localized in microsomes while CoQ is mainly localized in mitochondria; in PC12 cells added CoQ10 also localized in mitochondria, contrary to α-tocopherol.
The 3rd and 4th sessions were dedicated to metabolic aspects of CoQ.
In the third session Takayuki Takahashi (Kobe) provided important evidence of the major role of the cytosolic NADPH quinone reductase, previously discovered by Kishi’s group, in reducing intracellular non-mitochondrial CoQ10 to its antioxidant form, showing that this enzyme is distinct from other potential quinone reducing enzymes; the quinone reductase was purified and characterized as a 40 kDa protein. Lars Gille (Vienna) showed that the cyclization product of CoQ10, ubichromanol-10, yields by oxidation a compound hydroxyl-substituted in the side chain, having strong antioxidant properties when reduced and also behaving as a good substrate for Complex III. Yorihiro Yamamoto (Tokyo) searching for a putative CoQ-binding protein involved in transfer of the quinone from the sites of biosynthesis to other cellular districts, isolated from urine a CoQ-binding protein with high specificity for long-chain CoQ homologs and also present in human tissues, thus fitting that putative role. Makoto Kawamukai (Matsue) reported his extensive studies on CoQ10 biosynthesis in the fission yeast Schizosaccharomyces pombe by constructing deletion mutants of the different enzymes involved. The deletion mutant genes could be complemented by analogous human and plant genes, showing the similarity of the biosynthetic pathways of species being phylogenetically far away.
In the fourth session Catherine Clarke (Los Angeles) described the puzzling results obtained by feeding the nematode Caenorhabditis elegans with E. coli devoid of its CoQ homolog Q8, resulting in a significant life span extension; repletion of CoQ10 in the nematode did not reverse the life span extension, indicating that it did not depend on absence of CoQ per se; actually any treatment impairing the respiratory chain of the bacterium resulted in life span prolongation, suggesting a toxic effect of a functional respiratory chain (could this be due to ROS production?). Gustav Dallner (Stockholm) reported that CoQ epoxides generated by UV irradiation of the quinone inhibit cholesterol biosynthesis and up-regulate CoQ10 biosynthesis; the latter action at the transcriptional level is shared by tocotrienol epoxides. This is a very important observation, since stimulation of CoQ10 biosynthesis may overcome the difficulties in absorption and tissue uptake after oral administration. Placido Navas (Seville) provided evidence of transcriptional regulation of CoQ biosynthesis in a model of cells treated with the anti tumour agent camptothecin: treated cells had an enhanced NFkB-dependent transcription. This is the first demonstration of NFkB-dependent transcriptional regulation of CoQ biosynthesis in humans and opens new perspectives in understanding and treating mitochondrial diseases and aging. Finally Michio Hirano (New York) reviewed syndromes caused by CoQ10 deficiency due to defects of its biosynthesis; these diseases have been recognized only recently and are sensitive to early CoQ10 administration.
Section 5 was devoted to the treatment of cardiovascular disease by Coenzyme Q10.
F. Rosenfeldt (Melbourne) reported a prospective randomised clinical trial in which patients undergoing heart surgery were given preoperative Coenzyme Q10 together with antioxidants and fish oil for two weeks before and one month after surgery. The treated group of patients had reduced cardiac damage, reduced rate of heart arrhythmias and a one day shorter length stay in hospital. P. Langsjoen from Texas reported his use of ubiquinol, the reduced form of Coenzyme Q10 in treating patients with heart failure. Ubiquinol was used mainly in patients who did not respond to ubiquinone. The results in 7 patients were very encouraging with much higher blood levels and an improved clinical response compared to ubiquinone. Patients with heart failure appear to have reduced function the gastrointestinal system probably due to oedema of the gut. For reasons which are not clear, ubiquinol is better absorbed and for the same dose provides blood levels which are double that of ubiquinone. R. Belardinell, Littarru and co-workers from Ancona studied the effect of Coenzyme Q10 on endothelial function and extracellular superoxide dismutase (SOD). They found that Coenzyme 1Q10 improved endothelial function and enhanced levels of extracellular SOD possibly by gene induction.
Sven Mortensen reported on the progress to date with the large multinational Coenzyme Q10 trial in heart failure patients (Q-SYMBIO). This is potentially the most important trial of Coenzyme Q10 in cardiovascular disease ever to be carried out. It is planned to enrol 550 patients. It has been going for several years and still requires more patients to be enrolled. Evaluation of the effect on heart failure will take place at 16 weeks and again at two years. The trial is being funded by the Coenzyme Q10 Association and Pharma Nord. Final data is to be presented in 2009. Chris Florkowski from New Zealand presented data from a study of heart failure patients in which various biochemical predictors of severity of failure and response to therapy were used. In the “Battlescarred Cohort” trial, BNP was used as a marker of response to therapy and a predictor of survival. Surprisingly when serum Coenzyme Q10 levels were measured these were a better predictor of long term survival than the gold standard, BNP. Furthermore, when Coenzyme Q10 (high levels) and BMP (low levels) were combined, an even better predictor of survival and response to therapy was obtained.
In section six Mancinelli and Littarru used a combation of Coenzyme Q10 with propionyl-L-carnitine, and omega-3 fatty acids in cardiomyopathic hamstersHamsters and found beneficial affect on heart failure. This basic science study gives a scientific background for the common practice among clinicians of combining Coenzyme Q10 with other metabolic agents in patients with cardiovascular disease. Adarsh and co-workers have used Coenzyme Q10 in a novel application namely hypertrophic cardiomyopathy. Their study compared Coenzyme Q10 with conventional treatment and made the important finding that Coenzyme Q10 was able to reduce the outflow tract gradient, and improve diastolic function. Kirsten Brishmar reported that in patients with Type II Diabetes, one of the important predictors of the difference in severity of cardiovascular disease between females and males was the greater oxidative stress and the reduced antioxidant response in females compared to males.
In section eight Teran gave a follow-up to his previous presentation at the last Coenzyme Q10 Conference the effect of Coenzyme Q10 in preeclampsia studied in Ecuador. Coenzyme Q10 given daily for 20 weeks before delivery produced a significant reduction in the incidence of pre-eclampsia. Studies from Kaneka Corporation showed that Coenzyme Q10 was very non-toxic in rats. In humans it was concluded that the observed safety level for Coenzyme Q10 was 1200 mg per day, but this was probably a conservative estimate. Studies from the Nisshin Company show favourable absorption characteristics for a water soluble type Coenzyme Q10 powder and appeared to show improved uptake compared to lipid soluble Coenzyme Q10.
The Conference concluded as usual with presentations on the effect of Coenzyme Q10 in ameliorating the adverse affect of Coenzyme Q10 on oxidative stress in skin in induced by ultraviolet light. The appeared to be a reduction in wrinkle severity of the application of Coenzyme Q10 skin cream.
Giorgio Lenaz and Franklin Rosenfeldt
Dr. F.Crane and Prof. G.P. Littarru in Kobe
