Review
Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

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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.

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.

Section snippets

Functions of Coenzyme Q and an Overview of Its Biosynthesis

Coenzyme Q (CoQ; see Glossary and Box 1) plays a key role in an increasing number of biological processes, human diseases, and therapeutic regimens. While CoQ was discovered 60 years ago in Madison, Wisconsin [1] and Cambridge, England [2], gaps in our knowledge of CoQ biosynthesis, metabolism, and transport continue to limit our understanding of CoQ’s role in human disease and our ability to treat these diseases. Spurred by an influx of new experimental technologies merged with traditional

CoQ Head Group Biosynthesis

In mammals, the CoQ head group is derived from the essential amino acid phenylalanine, which is converted into tyrosine (Tyr) and, subsequently, 4-hydroxybenzoate (4-HB) 31, 32, 33, but the responsible enzymes are unidentified (Figure 2). A Tyr-to-4-HB pathway also operates in yeast [34]. However, unlike mammals, bacteria and yeast can produce 4-HB de novo through the shikimate pathway 30, 35, 36, 37, 38. Yeast can also use p-aminobenzoate (pABA) as an alternative head group precursor 39, 40.

Biosynthesis and Attachment of the Polyisoprenoid Tail

In mammals, the isoprene subunits for CoQ biosynthesis are generated through the mevalonate pathway 32, 44, 45, 46, stitched together by head-to-tail polymerization 47, 48, and attached to the head group via an electrophilic aromatic substitution (EAS) [49] (Figure 2). The responsible prenyltransferases Coq1p (PDSS1 and PDSS2) and Coq2p (COQ2; see Glossary and Box 1 for ‘COQ’ nomenclature) are localized to the inner mitochondrial membrane 25, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, a key point

The Terminal Stage of CoQ Biosynthesis – Head Group Modifications

In the terminal stage of CoQ biosynthesis, the head group is modified by a decarboxylation and a series of hydroxylations and methylations (Figure 2). In bacteria and yeast, the added methyl groups and hydroxyl groups derive from S-adenosyl methionine (SAM) [62] and O2 63, 64, respectively, and the same is predicted to be true in mammals. The proposed order of these reactions is based on isolation of CoQ intermediates from various strains of bacteria 65, 66, 67, 68, 69 and yeast 52, 53, 70, 71,

The CoQ Biosynthetic Complex

The enzymes in the terminal phase of CoQ biosynthesis form a biosynthetic complex termed complex Q (or the ‘CoQ-synthome’), which is located on the matrix face of the inner mitochondrial membrane.

The presence of a yeast CoQ biosynthetic complex was initially suggested by genetic studies that showed interdependence between Coq proteins: deleting any one of the genes coq39 caused depletion of numerous Coq proteins and accumulation of the same CoQ precursor, polyprenyl-hydroxybenzoate 72, 111, 112

Transmembrane Transport of Polar Precursors and Proteins

The precursors for building CoQ are negatively charged small molecules that cannot passively cross the inner mitochondrial membrane (Figure 2). How these polar CoQ precursors are transported from their site of production outside of mitochondria into the mitochondrial matrix is unclear.

The COQ proteins, which are encoded by nuclear DNA, must also be transported into the mitochondrial matrix. Mitochondrial protein import and processing is a complex process that can help coordinate and regulate

Uncharacterized Proteins in CoQ Biosynthesis

A number of genes that support CoQ biosynthesis encode proteins of unknown molecular function. These CoQ-related mitochondrial uncharacterized (x) proteins (MXPs) include COQ4, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COQ10A, COQ10B, and Coq11p.

Concluding Remarks and Future Perspectives

In recent years, the known functions of CoQ in human health and disease have expanded, rekindling the drive to fully define its biosynthesis. CoQ now has numerous defined functions outside of its primary role in mitochondrial OxPhos, including regulation of mitochondrial and possibly extramitochondrial functions (Figure 1). Likewise, human diseases with links to CoQ biosynthesis have expanded to include common diseases such as Parkinson’s disease, rare diseases such as a cerebellar ataxia, and

Acknowledgments

We thank all members of the Pagliarini Lab, especially fellow ‘Q Branch’ colleagues Andrew Reidenbach and Danielle Lohman, for helpful discussions. This work was supported by National Institutes of Health (NIH) grants R01GM112057 and R01GM115591 (to D.J.P.); and Ruth L. Kirschstein NRSA F30AG043282 (to J.A.S.).

Glossary

Complex Q (CoQ-synthome)
complex Q, also known as the CoQ-synthome, is the biosynthetic complex that produces CoQ.
CoQ
coenzyme Q (CoQ) is the redox-active lipid product of the biosynthetic pathway discussed here. See Box 1 for further explanations of CoQ nomenclature.
COQ5
COQ5 is an example of a human enzyme required for CoQ biosynthesis.
Coq5p
Coq5p is an example of a yeast enzyme required for CoQ biosynthesis.
MXP
a mitochondrial uncharacterized (x) protein (MXP) is a protein that localizes to

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