Abstract
Coenzyme Q (CoQ, ubiquinone) is a ubiquitous redox‐active lipid that is required for oxidative phosphorylation, acts as a lipophilic antioxidant, and is a critical cofactor for numerous other processes, such as uridine biosynthesis and fatty acid oxidation. Primary defects in CoQ biosynthesis cause a variety of phenotypes, from nephropathy and myopathy to fatal multiorgan disease. Secondary defects in CoQ levels have been implicated in the pathophysiology of many common conditions, such as neurodegenerative diseases, cardiomyopathies, diabetes, and aging. Unfortunately, exogenous oral supplementation of CoQ aimed at alleviating or preventing disease is difficult due to its large molecular weight and hydrophobicity. Only 2% of orally administered CoQ reaches the bloodstream, and less than 15% of the CoQ in the blood becomes incorporated into mitochondria in tissues; therefore, is often impossible for patients reach an effective dose, even when taking grams of CoQ daily. More efficient means of delivering exogenous CoQ to mitochondria, its main site of action, need to be developed. Here, we describe the synthesis and evaluation of an initial set of compounds designed to deliver CoQ in larger quantities selectively to mitochondria. These compounds incorporate a mitochondria‐targeting triphenylphosphonium (TPP) moiety attached to CoQ through a reversible linker, and are designed to accumulate in mitochondria and be cleaved to release native CoQ. Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produced CoQ, encouraging further development. Our ongoing efforts include assessing the efficacy of these compounds in rescuing CoQ‐deficient cells, and further optimizing design features to further promote effective cleavage and mitochondrial localization while minimizing toxicity.
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