CoQ₁₀ Deficient Endothelial Cell Culture Model for the Investigation of CoQ₁₀ Blood-Brain Barrier Transport

Primary coenzyme Q₁₀ (CoQ₁₀) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ₁₀ supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ₁₀ supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ₁₀ across the blood-brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ₁₀ transport across the BBB, using normal and pathophysiological (CoQ₁₀ deficient) cell culture models. The study identifies lipoprotein-associated CoQ₁₀ transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no "net" transport across the BBB. In the CoQ₁₀ deficient model, BBB tight junctions were disrupted and CoQ₁₀ "net" transport to the brain side increased. The addition of anti-oxidants did not improve CoQ₁₀ uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ₁₀ deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ₁₀ distribution across the BBB. The results imply that the uptake of exogenous CoQ₁₀ into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters.