A bioluminescent-based imaging probe for noninvasive longitudinal monitoring of CoQ10 uptake in vivo

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PROJECT SUMMARY Coenzyme Q10 (CoQ10) is a potent energy transfer molecule and a central cofactor in oxidative phosphorylation present in both cell membranes and mitochondria. CoQ10 is also known as a powerful anti-inflammatory and antioxidant agent that protects the tissues from the damage resulting from the activation of inflammatory signaling pathways and free radicals. It is naturally synthesized at high levels in the liver, heart, and kidneys. However, the ability of the body to synthesize its own CoQ10 significantly decreases with age. In addition to the regular aging process, significant decrease in CoQ10 levels have been identified in a number of human pathologies. Therefore, nutritional supplementation with CoQ10 provides a powerful tool to maintain its sufficient levels in the body with the goal to improve human health and reduce the risk of chronic diseases. In this context, multiple clinical trials revealed potential benefits of CoQ10 supplementation in cardiovascular diseases, neuronal and muscular degenerative diseases, statin-induced myopathy, high blood pressure, migraine, cancer, and many others. However, the variable success in the outcomes of many of such clinical trials is thought to be due to the lack of knowledge of the biological process determining cellular uptake, gastrointestinal absorption, and subsequent bioavailability of CoQ10. These unresolved issues significantly slow down clinical translation and further expansion of CoQ10 therapeutic applications. Thus, it is of critical importance to understand the biological processes that regulate CoQ10 uptake and to optimize its oral bioavailability, which remains to be one of the main challenges in CoQ10 supplementation. However, the progress of studying exogenous CoQ10 fluxes is significantly hampered by the lack of tools and no imaging techniques currently exist for noninvasive longitudinal monitoring of CoQ10 uptake. To address the unmet need for nutrient uptake imaging tools, we are currently developing a novel analytical platform based on a combination of versatile “click” chemistry reactions with noninvasive and ultrasensitive bioluminescent imaging (Optical platform for functional longitudinal imaging of metabolite uptake in vivo, 1-R01-EB034607-01A1). The method is independent of radioactive and/or short-lived isotopes, less costly, and allows longitudinal monitoring of metabolite absorption. While the first application of this approach was successfully validated by us using glucose and nicotinamide riboside, a form of vitamin B3, as an example (Nat Methods, 2019 and Biosens. Bioelectron. 2023), we are now expanding this technology to study uptake of different amino acids, fatty acids, and nucleosides, which all play a central role in many human pathologies. Since the design of the probes is based on noninvasive imaging, more data could be collected from a single animal enabling better reproducibility. Here, we propose to apply this versatile method to develop a novel imaging tool for noninvasive, longitudinal measurements of CoQ10 uptake both in vitro and in vivo. This novel probe will provide a unique opportunity for understanding CoQ10 uptake, tissue distribution, and will become a valuable tool for optimizing its oral bioavailability.