Interaction between the ins/IGF-1 and p38 MAPK signaling pathways in molecular compensation of sod genes and modulation related to intracellular ROS levels in C. elegans

摘要

Superoxide dismutases, which catalytically remove intracellular superoxide radicals by the disproportionation of molecular oxygen and hydrogen peroxide, are encoded by thesod-1to-5genes in the nematodeC. elegans. Expression of thesodgenes is mutually compensatory for the modulation of intracellular oxidative stress during aging. Interestingly, several-fold higher expression of thesod-1to-4was induced in asod-5deletion mutant, despite the low expression levels ofsod-5in wild-type animals. Consequently, this molecular compensation facilitated recovery of lifespan in thesod-5mutant. In previous reports, two transcription factors DAF-16 and SKN-1 are associated with the compensatory expression ofsodgenes, which are downstream targets of the ins/IGF-1 and p38 MAPK signaling pathways activated under oxidative and heavy metal stresses, respectively. Here, we show that p38 MAPK signaling regulates induction of not only the direct expression ofsod-1,-2and-4but also the indirect modulation of DAF-16 targets, such assod-3and-5genes. Moreover, a SKN-1 target, the insulin peptide geneins-5, partially mediates the expression of DAF-16 targets via p38 MAPK signaling. These findings suggest that the interaction of ins/IGF-1 and p38 MAPK signaling pathways plays an important role in the fine-tuning of molecular compensation amongsodgenes to protect against mitochondrial oxidative damage during aging.