CONICET | Buscador de Institutos y Recursos Humanos

Lipoic acid (LA) is a universally distributed sulfur containing cofactor. It is essential for the functioning of multienzymatic complexes involved in oxidative and one-carbon metabolism, and a potent antioxidant. Here we show that Caenorhabditis elegans is able to synthesize LA and thus, this nematode could be a valuable model to study the metabolism of this coenzyme in multicellular organisms. By in silico analyses we found two nematode proteins with considerable identity percentages with bacterial, human and yeast enzymes involved in lipoylation. M01F1.3 has homology with lipoate synthases, while ZC410.7 has sequence similarity with octanoyltransferases. In both cases RNA interference (RNAi) experiments performed in N2 strain resulted in larval arrest and lower resistance to oxidative stress compared to control animals. It was confirmed by Western blot analyses that these treated worms had reduced protein lipoylation levels. The arrested phenotype could not be rescued by the addition of exogenous LA, which lead us to think that synthesis of LA is essential in the worm. Besides, complementation assays with M01F1.3 rescue a Bacillus subtilis lipoate synthase mutant. In the other hand, expression of ZC410.7 functionally complement a yeast lip2 mutant, deficient in octanoyltransferase activity. Taken together, these results demonstrate that M01F1.3 and ZC410.7 are the C. elegans lipoate synthase and octanoiltransferase, respectively, and that lipoate synthesis is essential for the correct development of the worms. Human patients with defects in protein lipoylation suffer from severe neurological disorders and they receive treatments just to alleviate symptoms. Elucidation of how proteins become lipoylated in the nematode C. elegans would contribute to the understanding of the process in humans and the development of new therapies.