Coenzyme A as a central player in cellular and tissue homeostasis

PhD ceremony: Ms. K.A. Siudeja, 12.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Coenzyme A as a central player in cellular and tissue homeostasis

Promotor(s): prof. O.C.M. Sibon

Faculty: Medical Sciences

Coenzyme A (CoA) is an important metabolite present in almost all living organisms. It is estimated that CoA acts as a cofactor in 4 % of all known enzymatic reactions. Although the involvement of CoA in these numerous reactions is well known, the consequences of impaired CoA metabolism have not been studied in detail. At the same time, it is known that in humans mutations in pantothenate kinase (PANK), the first enzyme in the CoA de novo biosynthesis pathway, cause the severe neurodegenerative disease PKAN (pantothenate kinase-associated neurodegeneration). The pathology of PKAN is complex and poorly understood, and no cure exists for this disease.

In this thesis we used different techniques and strategies to address the consequences of impaired CoA metabolism on the cellular and the whole-organism level. We used genetic and biochemical techniques to interfere with PANK activity in Drosophila melanogaster and human cell culture models of PKAN. We showed that the consequences of impaired CoA synthesis are far-reaching and involve many processes, which until now have not been directly linked to CoA metabolism. We address the involvement of CoA metabolism in the progression through the cell cycle, in posttranslational modification of proteins by acetylation of lysine residues or in the dynamic regulation of the actin cytoskeleton.

Altogether the results presented here not only contribute to increased fundamental cell biology knowledge, but may also serve for a better understanding of the pathophysiology of PKAN and suggest possible directions for the development of future PKAN therapies.