Coenzyme Q biochemistry and biosynthesis

HighlightsCoenzyme Q (CoQ) plays major roles in cell metabolism beyond transferring electrons in the ETC, including acting as an antioxidant and enzyme cofactor. Its ubiquitous presence in cellular membranes suggests that more roles for CoQ are yet to be discovered.Recent studies have identified a role for plasma membrane CoQ in combating ferroptosis. These findings have reinvigorated efforts to understand how CoQ is transported throughout the cell.CoQ is synthesized in a metabolon-like complex that is proximal to mitochondrial contact sites, which may be important for facilitating CoQ transport out of mitochondria.The CoQ biosynthetic pathway remains incompletely characterized, with multiple enzymatic and transport steps lacking associated proteins. Discovery efforts have met challenges including enzyme redundancy, essentiality, and hydrophobic barriers associated with synthesizing CoQ.AbstractCoenzyme Q (CoQ) is a remarkably hydrophobic, redox-active lipid that empowers diverse cellular processes. Although most known for shuttling electrons between mitochondrial electron transport chain (ETC) complexes, the roles for CoQ are far more wide-reaching and ever-expanding. CoQ serves as a conduit for electrons from myriad pathways to enter the ETC, acts as a cofactor for biosynthetic and catabolic reactions, detoxifies damaging lipid species, and engages in cellular signaling and oxygen sensing. Many open questions remain regarding the biosynthesis, transport, and metabolism of CoQ, which hinders our ability to treat human CoQ deficiency. Here, we recount progress in filling these knowledge gaps, highlight unanswered questions, and underscore the need for novel tools to enable discoveries and improve the treatment of CoQ-related diseases.