Current Drug Targets, 2010, 11, 00-00 1 1389-4501/09 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders M. Mancuso * , D. Orsucci, L. Volpi, V. Calsolaro and G. Siciliano Department of Neuroscience, Neurological Clinic, University of Pisa, Italy Abstract: Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has been implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency. Key Words: Coenzyme Q10, CoQ10 deficiency, idebenone, mitochondria, mitochondrial diseases, neurodegeneration, statins. INTRODUCTION Coenzyme Q10 (CoQ10), or ubiquinone, is an endogenously synthesized lipid, which shuttles electrons from complexes I (NDSH: Ubiquinone reductase) and II (succinate: ubiquinone reductase) and from the oxidation of fatty acids and branched-chain aminoacids (via flavin-linked dehydrogenases) to complex III (ubiquinol cytochrome c oxidase) of the mitochondrial respiratory chain (electron transport chain, ETC) [1] (Fig. 1). The reduced form of CoQ10 known as ubiquinol also has antioxidant properties, protecting membrane lipids and proteins and mitochondrial deoxyribonucleic acid (mtDNA) against oxidative damage [1]. Intracellular synthesis is the major source of CoQ10, although a small proportion is acquired through diet (i.e. oily fish, organ meats such as liver, and whole grains). CoQ10 biosynthesis depends on the mevalonate pathway (Fig. 2), a sequence of cellular reactions leading to farnesyl pyrophosphate, the common substrate for the synthesis of cholesterol, dolichol, dolichyl posphate, CoQ10, and for protein prenylation (a post-translational modification necessary for the targeting and function of many proteins) [1]. Cells synthesize CoQ10 de novo, starting with synthesis of the parahydroxybenzoate ring and the polyisoprenyl tail, which anchors CoQ10 to membranes [1] (Fig. 3). The length of this tail varies among different organisms. In humans, the side chain is comprised of ten isoprenyls producing CoQ10 [1]. In healthy individuals, oral administration of CoQ10 has been reported to improve subjective fatigue sensation and physical performance during fatigue-inducing workload trials [2]. CoQ10 has been widely used for the treatment of mitochondrial disorders (MD) and other neurodegenerative disorders, as well as its synthetic analogue, idebenone [3]. Potential treatment indications for the use of CoQ10 include migraine [4, 5], chronic tinnitus aurium [6], hypertension [7], heart failure and atheroscle- rosis [8], although the role of CoQ10 in such conditions is still an *Address correspondence to this author at the Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy; Tel: 0039- 050-992440; Fax: 0039-050-554808; E-mail mmancuso@inwind.it open question. CoQ10, which may ameliorate endothelial dysfunc- tion [9], is an independent predictor of mortality in chronic heart failure, and there is a rationale for controlled intervention studies with CoQ10 in such condition [9, 10]. Although CoQ10 is also used for the prevention and treatment of cancer, there is as yet no convincing evidence of its efficacy treatment of this order[8]. No absolute contraindications are known for CoQ10, and adverse effects are rare [8]. Mild dose-related gastrointestinal dis- comfort is reported in <1% of patients [8]. Potential interactions with warfarin causing decreased international normalized ratio (INR) have been suggested [8]. Its various formulations demons- trate variation in bioavailability and dosage consistency, and there is a serious possibility that patients may have been treated sub- optimally [8]. It is important to use brands that have passed independent testing for product purity and consistency [8]. During CoQ10 supplementation plasma CoQ10 levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ10 absorption [10]. However, plasma levels may not reflect that of the cell and other surrogates such as blood mononuclear cells may be more appropriate [11]. MITOCHONDRIAL COMPARTMENT Mitochondria are dynamic and pleomorphic organelles, which evolved from the aerobic bacteria which about 1.5 billion years ago populated primordial eukaryotic cells, thus endowing the host cells with oxidative metabolism (much more efficient than anaerobic glycolysis) [12]. Mitochondria are composed of a smooth outer membrane surrounding an inner membrane of significantly larger surface area that, in turn, surrounds a protein-rich core, the matrix [12]. They contain two to ten molecules of mtDNA [12]. In humans, the mtDNA is transmitted through maternal lineage [12]. The most crucial task of the mitochondrion is the generation of energy as adenosine triphosphate (ATP), by means of the ETC. The ETC is required for oxidative phosphorylation (which provides the cell with the most efficient energetic outcome in terms of ATP production), and consists of four multimeric protein complexes located in the inner mitochondrial membrane [12]. The ETC also