Reduced TORC1 signaling abolishes mitochondrial dysfunctions and shortened chronological lifespan of Isc1p-deficient cells.

The target of rapamycin (TOR) is an important signaling pathway on a hierarchical network of interacting pathways regulating central biological processes, such as cell growth, stress response and aging. Several lines of evidence suggest a functional link between TOR signaling and sphingolipid metabolism. Here, we report that the TORC1-Sch9p pathway is activated in cells lacking Isc1p, the yeast orthologue of mammalian neutral sphingomyelinase 2. The deletion of or abolishes the premature aging, oxidative stress sensitivity and mitochondrial dysfunctions displayed by Δ cells and this is correlated with the suppression of the autophagic flux defect exhibited by the mutant strain. The protective effect of deletion, as opposed to that of deletion, is not associated with the attenuation of Hog1p hyperphosphorylation, which was previously implicated in Δ phenotypes. Our data support a model in which Isc1p regulates mitochondrial function and chronological lifespan in yeast through the TORC1-Sch9p pathway although Isc1p and TORC1 also seem to act through independent pathways, as ΔΔ phenotypes are intermediate to those displayed by Δ and Δ cells. We also provide evidence that TORC1 downstream effectors, the type 2A protein phosphatase Sit4p and the AGC protein kinase Sch9p, integrate nutrient and stress signals from TORC1 with ceramide signaling derived from Isc1p to regulate mitochondrial function and lifespan in yeast. Overall, our results show that TORC1-Sch9p axis is deregulated in Isc1p-deficient cells, contributing to mitochondrial dysfunction, enhanced oxidative stress sensitivity and premature aging of Δ cells.