Pathogenesis of primary and secondary Coenzyme Q deficiency

Coenzyme Q (CoQ) is a small molecule and is an essential component of the mitochondrial respiratory chain (RC). A lack of Coenzyme Q cause CoQ deficiency, a severe, often fatal, mitochondrial disorder. Three forms of Coenzyme Q deficiencies are known to mainly affect kidneys, cerebellum and muscles respectively. All are caused by mutations in genes that can (primary CoQ deficiencies) or cannot (secondary CoQ deficiencies) be involved in CoQ biosynthesis. Patients are usually and successfully treated with doses of CoQ. This therapy is largely effective even in patients with secondary CoQ deficiencies. It’s already known that defects in the mitochondrial respiratory chain are often associated with the lack of CoQ, but the reasons behind this association are still unclear. We have now discovered that in mammalian cells the enzymes that synthesize CoQ are organized into a complex (QBC) which interacts with the components of the RC. This interaction is essential for efficient CoQ biosynthesis. This explains why defects in the RC may inhibit CoQ biosynthesis. The goal of this project is to fully understand the structure of the QBC and its functional relationships with other mitochondrial proteins. To develop simple models that may aid us in understanding the mechanisms that cause both primary and secondary CoQ deficiencies, and to develop novel therapeutic approaches which may integrate oral CoQ supplementation. Finally we aim to discover the genetic factors that may predispose patients to develop secondary CoQ deficiency. Overall this project will benefit researchers, because it will increase our knowledge on a critical cellular pathway, but it will have a tremendous impact on patient care, because the information obtained, will improve the way we treat CoQ deficient patients, and it will help us identify those individuals who are likely to develop secondary deficiencies and thus could benefit the most from treatment.