A Model for the Function of COQ9: the Isoprenoid‐Precursor Presenter

Abstract

Coenzyme Q (CoQ) is a vital part of the electron transport chain that is synthesized de novo in mitochondria by the combined action of at least 10 proteins (COQ1–10). Defects in CoQ biosynthesis lead to primary CoQ deficiency, which has serious human health implications ranging from encephalomyopathy to cerebellar ataxia. Coenzyme Q biosynthesis protein 9 (COQ9) is a crucial part of this pathway, but its exact role remains unknown. A recently‐published manuscript from our lab revealed that COQ9 contains a small‐molecule binding domain, which co‐crystallized with a phospholipid, and demonstrated that COQ9 associates functionally and physically with COQ7. COQ7 catalyzes the hydroxylation of the CoQ intermediate, demethoxy‐CoQ (DMQ), in one of the last steps of CoQ biosynthesis. CoQ and its isoprenylated intermediates are highly hydrophobic, with mature CoQ residing predominantly within the inner mitochondrial membrane, while the CoQ biosynthetic enzymes are peripheral. This apparent lack of accessibility produces a biosynthetic barrier that we envision may be overcome by a protein capable of chaperoning and presenting lipid intermediates to the CoQ biosynthetic enzymes. Due to its ability to bind lipids, its physical association with COQ7, and the accumulation of DMQ in both yeast and mice harboring mutant versions of COQ9, we hypothesize that COQ9 fills this role. To test this hypothesis, I have enriched DMQ from bacteria using organic lipid extraction and column chromatography, and have optimized assays using liposomes to test the isoprenoid transport abilities of COQ9. In this presentation, I discuss the results of these experiments and the insights they have provided toward elucidating the biochemical role of COQ9 in CoQ biosynthesis, understanding CoQ biosynthesis as a whole, and ultimately treating CoQ deficiency.