The lipoyl-relay pathway is essential for development in Caenorhabditis elegans

MANSILLA, MC; DE MENDOZA, D; LAVATELLI, A

Congreso; Second Latin American Worm Meeting; 2020

Lipoic acid (LA) is a sulfur containing cofactor covalently bound to cognate key enzymes that are essential for several redox reactions in all three domains of life. Inherited mutations in human lipoyl synthase (LIAS), octanoyltransferase (LIPT2) and amidotransferase (LIPT1), impair LA biosynthesis causing severe psychomotor retardation and several intractable brain damages. Although these pathologies have been attributed mainly to deficiency in protein lipoylation, many aspects of this essential pathway are still obscure and patients receive treatment just to alleviate symptoms. We found by in silico analyses Caenorhabditis elegans proteins possibly involved in this post-transductional modification. Worms subjected to RNA interference (RNAi) against M01F1.3 and ZC410.7 manifest larval arrest in the second generation. The arrest was not rescued by LA supplementation indicating that endogenous synthesis of LA is essential for C. elegans development. Remarkably, expression of the enzymes M01F1.3, ZC410.7 and C45G3.3 completely rescued bacterial or yeast mutants affected in different steps of the lipoylation pathway. In this study we demonstrate that C. elegans is able to synthesize LA de novo via a lipoyl-relay pathway and thus, that this nematode could be a valuable model to study protein lipoylation in humans and to develop new therapies.