CONICET | Buscador de Institutos y Recursos Humanos

Lipoic acid is a universally distributed sulfurcontaining cofactor. It is derived from octanoic acid and it is essential forthe functioning of multienzymatic complexes involved in oxidative andone-carbon metabolism. It is also a potent antioxidant. The ways in whichprokaryotes proteins become post-translationally modificated with LA are verywell understood. On the contrary, eukaryotes lipoylation pathways are notclearly characterized, even in simple organisms such as yeast. There areseveral reports of human patients defective in protein lipoylation who died inearly life or survived but with severe neurological disorders. Treatment forthose patients was just to alleviate symptoms. Our goal is to elucidate howproteins become lipoylated in the nematode Caenorhabditiselegans in order to understand the process in humans and develop newtherapies. By complementation assays we have already demonstrated that C. elegans M01F1.3 protein is the wormlipoate synthase. We also reported that its depletion by interference RNA(RNAi) caused a larval arrest phenotype in the second generation of N2 worms.Here we show that this experiment carried out in a RNAi hypersensitive strainalso generates a larval arrest phenotype, but in the first generation(p<0.01). Notably, the addition of exogenous lipoate was unsuccessful torestore the normal life cycle. Worms subjected to RNAi treatment that wereincubated in presence of Fe (II) exhibited a lower resistance to oxidativestress compared to control animals (p<0.05). RNAi experiments were alsoperformed with strains that allow tissue-specific knockdown, and we found thatM01F1.3 expression is necessary in neurons for the correct development of worms.These results support that M01F1.3 is essential for the correct development ofthe worms and suggest that its expression is crucial in neurons.