Abstract
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.
Highlights
Coenzyme Q10 (CoQ10) plays an important role in oxidative phosphorylation where it acts as an electron carrier in the mitochondrial respiratory chain (MRC)
Primary CoQ10 deficiencies stem from mutations in genes required for CoQ10 biosynthesis while secondary deficiencies are associated with diseases that do not result from a genetic defect in the CoQ10 biosynthetic pathway and include disorders such as primary MRC deficiencies and organic acidemias [4]
Using pharmacological inhibitors of blood–brain barrier (BBB) lipoprotein transporters, we investigated their effect on CoQ10 transport, blocker of lipid transport-1 (BLT-1) inhibitor of scavenger receptor B1 (SR-B1) (Scavenger Receptor) mediated HDL uptake [15], the receptor-associated protein (RAP) inhibitor of the Low-Density Lipoprotein Receptor (LDLR) superfamily [16], including LRP-1, vLDLR, apoER2, and LDLR; and FPS-ZM1 inhibitor of the receptor for advanced glycation end products (RAGE) which opposes LRP-1 as part of apolipoprotein E-amyloid beta homeostasis [17]
Summary
Coenzyme Q10 (CoQ10) plays an important role in oxidative phosphorylation where it acts as an electron carrier in the mitochondrial respiratory chain (MRC). CoQ10 deficiencies are defined by decreased cellular CoQ10 content, and pathogenesis involves both reduced ATP production and increased ROS production [3]. Primary CoQ10 deficiencies stem from mutations in genes required for CoQ10 biosynthesis (nine genes have been identified [3]) while secondary deficiencies are associated with diseases that do not result from a genetic defect in the CoQ10 biosynthetic pathway and include disorders such as primary MRC deficiencies and organic acidemias [4]. A failure in CoQ10 biosynthesis could contribute to disease pathophysiology by causing a failure in energy metabolism and/or increased oxidative stress
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