Lipoic acid metabolism in Caenorhabditis elegans

LAVATELLI ANTONELA; MANSILLA MARÍA CECILIA; DE MENDOZA DIEGO

Buenos Aires

Congreso; Frontiers in Bioscience 3; 2018

Biomedicine Research Institute of Buenos Aires

Lipoic acid is a universally conserved cofactor and one of the most potent antioxidants present in cells. It is an organosulfur compound derived from octanoic acid necessary for the functioning of multienzymes complexes involved in oxidative and one-carbon metabolism. Lipoylation pathways have been studied for more than 50 years. Nevertheless, the eukaryotes pathways are just beginning to be understood. We inferred by in silico analyses which proteins would be involved in the Caenorhabditis elegans lipoylation pathway and verified their roles either by RNA interference (RNAi) assays or complementation tests. We found that C. elegans lipoate synthesis is essential for development, since knocking down the expression of the putative lipoylation enzymes led to larval arrest phenotypes. Supplementation with either lipoate or the products of the reactions catalyzed by the lipoate-dependent enzyme complexes was not able to restore the reproductive cycle of RNAi-treated animals. We also demonstrated that RNAi treated worms have reduced life span and lower oxidative stress resistance than control animals. By specific tissue RNAi experiments we found that blocking lipoate synthesis in neurons affect worm brood size. Human patients which present lipoylation defects suffered neurological disorders and they are subjected to treatments just to alleviate symptoms. Since our findings strongly suggest that the worm lipoate biosynthetic pathway is similar to that proposed for humans, unraveling the mechanisms by which lipoic acid deficiencies affect development in C. elegans could have important implications for better understanding pathological conditions associated with impaired protein lipoylation.