Disruption of the
nhx-2 gene, which codes for an intestinal Na+/H+ exchanger, leads to early larval arrest through a mechanism resembling starvation. We have hypothesized that the proton gradient established by NHX-2 is functionally coupled to intestinal H+/dipeptide cotransport by OPT-2. Here, we demonstrate that NHX-2 loss-of-function directly inhibits the uptake of fluorescent, labeled dipeptide substrate as well as the uptake of fluorescent, labeled glucose through an unknown transporter. We further demonstrate that dilution of dsRNA targeting the
nhx-2 message can modulate the intracellular pH (pHi) of the intestine, and that the
nhx-2- larval arrest phenotype and associated increase in lifespan are directly related to pHi. We hypothesize that pHi is a control mechanism for regulating cell growth through nutrient availability. To explore the mechanisms through which intestinal pHi might convey metabolic information to peripheral cells, a two gene loss-of-function analysis was performed using mutants in the well-studied insulin signaling pathway in combination with
nhx-2 RNAi; we then assessed larval development, post-adult lifespan, and the prevalence of fat stores in the intestine. To ask whether these cells respond to reduced pHi akin to many other types of stresses, the subcellular localization of DAF-16p and SKN-1p reporter genes were examined. Furthermore, since dauer formation is regulated by nutrient availability, we examined the pHi of the intestine during entry into and recovery from dauer phase. We demonstrate that dauer recovery requires the activity of NHX-2 and results in a transient acidification of the intestine. Our data suggests a complex regulatory network where pHi influences insulin signaling pathways to coordinate nutrient availability and cell growth. Finally, the initial results from a global RNAi screen for intestinal acidification identified a higher-than-expected number of gene products that act in the mitochondria, suggesting that intestinal pHi may provide a link between caloric restriction, mitochondria function, and insulin signaling.