Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge ‘omics’ approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases. A biosynthetic complex for producing CoQ was recently revealed in yeast and mammals. This complex likely contains proteins, lipids, and polar small molecules, but its precise composition, structure, and activities remain largely unknown. Multiple MXPs have been linked to CoQ biosynthesis, and multiple steps in the pathway are enabled by currently unidentified proteins. Recent progress was made toward understanding the biochemistry of a dehydrogenase, a deaminase, a lipid-binding protein, and a protein kinase-like enzyme in the CoQ pathway. CoQ biosynthesis spans multiple ‘omic’ planes – the metabolome, the lipidome, and the proteome – and thus has proven to be a prime target for investigation with emerging multiomic technologies. Mapping CoQ biochemistry recently spurred new therapeutic strategies.