CoQ(10) Deficient Endothelial Cell Culture Model for the Investigation of CoQ(10) Blood–Brain Barrier Transport

Primary coenzyme Q(10) (CoQ(10)) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ(10) 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 CoQ(10) supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ(10) across the blood–brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ(10) transport across the BBB, using normal and pathophysiological (CoQ(10) deficient) cell culture models. The study identifies lipoprotein-associated CoQ(10) 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 CoQ(10) deficient model, BBB tight junctions were disrupted and CoQ(10) “net” transport to the brain side increased. The addition of anti-oxidants did not improve CoQ(10) uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ(10) deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ(10) distribution across the BBB. The results imply that the uptake of exogenous CoQ(10) into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters.