Mitochondrial Coenzyme Q biosynthesis disorders human

ABSTRACT

Coenzyme Q₁₀ (CoQ₁₀) plays a pivotal role in oxidative phosphorylation (OXPHOS) as it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q₁₀ deficiency is a rare, but possibly treatable, autosomal recessive condition with four major clinical presentations, an encephalomyopathic form, a generalized infantile variant with severe encephalopathy and renal disease, a myopathic form and an ataxic form. The diagnosis of ubiquinone deficiency is supported by respiratory chain analysis and eventually by the quantification of CoQ₁₀ in patient tissues. We review here the quinone deficiency diseases as well as the clinical improvement after oral CoQ₁₀ therapy. The clinical heterogeneity of ubiquinone deficiency is suggestive of a genetic heterogeneity that should be related to the large number of enzymes, and corresponding genes, involved in ubiquinone biosynthesis.

INTRODUCTION

Coenzyme Q (CoQ, ubiquinone, UQ) is a lipophilic component located in the inner mitochondrial membrane that has a pivotal role in oxidative phosphorylation (OXPHOS). Indeed, CoQ shuttles electrons from complex I and complex II to complex III. Being in large excess compared to any other component of the respiratory chain (RC), it forms a kinetically compartmentalized pool, the redox status of which tightly regulates the activity of the dehydrogenases. CoQ also plays a critical function in antioxidant defenses. Ubiquinone is composed by a redox active benzoquinone ring connected to a long isoprenoid side chain. Ubiquinone is present in prokaryotes and eukaryotes but the length of its isoprenoid chain varies among species. Humans and rodents produce mainly CoQ₁₀ and CoQ₉ respectively, whereas Saccharomyces cerevisiae synthesizes CoQ₆ and Escherichia coli CoQ₈. In human, CoQ₁₀ is present in all tissues and cells but in variable amount. It ranges between 114 μg/g in heart to 8μg/g in lung¹. However, small amount of CoQ₉ (2-7%) are also synthesized in human tissues. Moreover, it has been shown in bovine brain that the concentration of ubiquinone varies among cells and regions of a specific organ.

CLINICAL PRESENTATION

Primary coenzyme Q₁₀ deficiency is a rare, clinically heterogeneous disorder of the respiratory chain. The first patient was described more than twenty years ago² and less than thirty patients have been further reported. CoQ₁₀ deficiency is presumably inherited as an autosomal recessive trait as all enzymes involved in ubiquinone biosynthesis pathway are nuclearly encoded and as patients are born from healthy parents.

Four major phenotypes have been previously described (i) an encephalomyopathic form characterized by exercise intolerance, mitochondrial myopathy, myoglobinuria, epilepsy and ataxia; (ii) a generalized infantile variant with severe encephalopathy and renal disease; (iii) a myopathic form with exercise intolerance, myoglobinuria, and myopathy; and (iv) an ataxic form, dominated by ataxia, seizures and either cerebellar atrophy or anomalies of the basal ganglia. However, since this first classification of ubiquinone deficiency, ...