Editorial Commentary Have No Fear , MitoQ 10 Is Here

The physical manifestation of a trait is a constant interplay between one’s genetic makeup and environmental factors. This notion has been substantiated by nutrigenomic studies demonstrating the benefits of nutritional supplements along the continuum between health and disease.1 More importantly, these studies have revealed the plasticity by which the genetic substrate can interact with various environmental components to either exacerbate or mitigate the manifestation of a disease process in those genetically predisposed. Focusing on cardiovascular disease, a vast literature has demonstrated that this disease process is associated with impaired energy production, increased oxidative stress, and cell calcium overload. To these ends, both clinical and animal studies have demonstrated nutrient deficiencies, integral to these processes, to be associated with cardiovascular disease and that these deficiencies represent independent predictors of increased morbidity and mortality.2,3 One cellular component that has received considerable attention regarding function and nutrient supplementation is the mitochondria. Mitochondria are responsible for cellular bioenergetics via oxidative phosphorylation. However, the perpetual transfer of electrons from one molecule to another within the mitochondria renders this organelle a major site for the genesis of reactive oxygen species (ROS).4 Although the mitochondria have antioxidant defenses,4 the disequilibrium between ROS production and ROS neutralization paves the way for disease manifestation. ROS damage to mitochondrial proteins, lipids, and DNA poses a serious detriment to the mitochondria. In particular, knockout experiments of key mitochondrial oxidative defenses are associated with the onset of cardiovascular disease, whereas their overexpression is capable of forestalling the onset of disease.5 Conversely, supplementation of specific antioxidants has been shown to mitigate the disease state in animal models.5 However, it is difficult to determine with alacrity the contribution that mitochondrial-derived ROS may have on cardiovascular disease.5 To this end, the work by Graham et al6 published in this issue of Hypertension demonstrated the extent that mitochondrial-derived ROS contributes to cardiovascular disease. Coenzyme Q10 (CoQ10) is an endogenous compound found in the inner mitochondrial membrane that is essential to electron transport and ATP production via the respiratory chain (Figure, (a)). In addition to its role in bioenergetics, supplementation with CoQ10 has been shown to inhibit thrombus formation and to reduce ROS7 (Figure, (b)). Both clinical and rodent studies have demonstrated moderate beneficial actions of CoQ10 in reducing blood pressure, decreasing blood glucose, forestalling myocardial damage secondary to chemotherapeutic administration, limiting tumor growth, enhancing endothelial function, and improving cognitive function in both Alzheimer’s and Parkinson patients.7 However, one of the major limiting factors in the use of CoQ10 as a supplement is its bioavailability and delivery to the source of ROS generation. Using a mitochondria-targeted lipophilic triphenylphosphonium cation covalently bound to ubiquinol, MitoQ10, Graham et al6 demonstrated that oral administration of this formulation of CoQ10 reduced blood pressure, increased the bioavailability of NO, and reduced cardiac hypertrophy in a rodent model genetically predisposed to high blood pressure and stroke. Moreover, mass spectrometry demonstrated significant ubiquinol content in liver, heart, carotid, and kidney tissues.6 Conversely, the lipophilic cation used to target ubiquinol to the mitochondria had no beneficial actions.6 Therefore, the significance of this work is 2-fold. First, it demonstrated the benefits of ubiquinol. Second, it demonstrated the enhanced delivery of CoQ10 to a specific target. In addition, this study reinforced the importance of CoQ10 supplementation. However, at the same time, these findings have raised some important questions regarding CoQ10. Although coenzyme Q10 is an essential component of the respiratory chain and protects the mitochondrial and cell membranes from lipid oxidation, it also functions as a cofactor for uncoupling proteins8 (Figure, (c)). Uncoupling proteins are, in essence, the molecular switch that change the end product of the respiratory chain from an ATP producer to that of heat generator.8 Several studies have demonstrated that uncoupling proteins reduce ROS and that CoQ10 is an essential cofactor for these uncoupling proteins.8 Therefore, CoQ10, along with uncoupling proteins, may play a role in ROS-dependent signaling pathways, and the ratio of oxidized:reduced CoQ10 may also play an important signaling role. This notion is of particular interest, because CoQ10 has been shown to be a potent gene regulator. Specifically, CoQ10 caused an increased expression of hundreds of genes in human cell lines.9 Although the molecular mechanisms whereby CoQ10 is imparting these pleiotropic effects has yet to be discerned,9 CoQ10 may have a more far-reaching action than simply as an antioxidant. Another important question raised by the study by Graham et al6 relates to who can benefit from this formulation of CoQ10 and what other circumstances would warrant its administration. By demonstrating the salutary actions of MitoQ10 in stroke-prone spontaneously hypertensive rats, Graham et al6 demonstrated the beneficial role of CoQ10 supplementation in a The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From University Hospitals, Mayfield Village Medical Center, Mayfield Village, Ohio. Correspondence to John C. Barbato, University Hospitals, Mayfield Village Medical Center, 730 SOM Center Rd, #170, Mayfield Village, OH 44143. E-mail [email protected] (Hypertension. 2009;54:222-223.) © 2009 American Heart Association, Inc.