COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating
Coenzyme Q biosynthesis requires the atypical kinase-like COQ8 proteins, whose ATPase activity streamlines the membrane-associated COQ metabolon, yet its molecular mechanism has remained unclear. Taking advantage of the tetrapod ancestral coenzyme Q biosynthetic machinery and liposomes mimicking the inner mitochondrial membrane, we show that COQ8A and COQ8B act as a streamlining factor for the coenzyme Q metabolon by engaging in loose protein-protein interactions and delivering insoluble biosynthetic intermediates. Structural bioinformatics and pathological-variant-driven mutagenesis reveal that coenzyme Q intermediates are recognized via their head-groups in a pocket whose access is gated by long-range conformational changes controlled by ATP hydrolysis. Finally, it is demonstrated that excess coenzyme Q suppresses binding of early-stage intermediates and thereby abolishes the streamlining effect of COQ8 on the metabolon. Together, these results support a model in which COQ8 functions as a biochemical coenzyme Q sensor that tunes coenzyme Q biosynthesis by coupling ATPase-driven intermediate chaperoning with feedback regulation by the final product. TeaserCOQ8 enhances coenzyme Q metabolic flux via ATP hydrolysis-driven chaperoning of biosynthetic intermediates.