CoQ biosynthetic pathway components form a supracomplex localized to ER-mitochondria contacts

Identification: Subramanian, Kelly


CoQ biosynthetic pathway components form a supracomplex localized to ER-mitochondria contacts
Kelly Subramanian1, Adam Jochem2, Samantha Lewis1, David Pagliarini2,3, Jodi Nunnari1,
1University of California, Davis; 2Morgridge Institute for Research; 3University of Wisconsin-Madison
In eukaryotes, the coenzyme Q biosynthetic pathway is housed within mitochondria and functions to produce coenzyme Q (CoQ) - an essential electron transporting component of the respiratory chain. The pathway is comprised of at least 13 proteins, which build CoQ from substrates derived from tyrosine and the extramitochondrial mevalonate pathway. Previously published biochemical and proteomic analyses indicate that a subset of CoQ pathway components interact to form a dynamic, multi-subunit complex associated with the matrix side of the mitochondrial inner membrane. We examined the spatial organization and dynamics of the CoQ biosynthetic complex in budding yeast using endogenously expressed functional fluorescently-tagged Coq proteins. Our data indicate that biosynthetic complex components uniquely localized to resolvable focal structures within mitochondria in cells. The relatively low cellular copy number of Coq-labeled foci suggests that these structures represent supramolecular assemblies of the complex. Consistent with the high evolutionary conservation of this pathway, we observed discrete Coq focal structures within mitochondria in human cells. In yeast, Coq foci formation was dependent on pathway components that are essential for CoQ production, suggesting that CoQ substrates are required for supracomplex formation. To test a role for substrate in supracomplex assembly, we utilized cells expressing an enzymatically inactive allele of Coq6 that can be bypassed by adding exogenous vanillic acid, a bihydroxybenzoic acid derivative. In these cells, Coq foci formation was strictly dependent on the presence of vanillic acid, indicating that supramolecular complex formation depends on substrate and/or substrate flux through the pathway. To gain insight into the function of the supracomplex, we examined its spatial localization relative to other cellular structures. Our analysis indicates that Coq foci were highly enriched at ER-mitochondria contacts. Thus, our data suggest a model where CoQ intermediates drive the formation of a supramolecular CoQ biosynthetic machine at ER-mitochondria contact sites to facilitate substrate influx and utilization as well as product distribution.


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