Sphingolipids and mitochondrial function, lessons learned from yeast

Background: Sphingolipids (SLs) are key components of cellular membranes, but also play an important role as signaling molecules in orchestrating both cell growth and apoptosis. In Saccharomyces cerevisiae, three complex SLs are present and hydrolysis of either of these species is catalyzed by the inositol phosphosphingolipid phospholipase C (Isc1p). Strikingly, mutants deficient in Isc1p display several hallmarks of mitochondrial dysfunction such as the inability to grow on a non-fermentative carbon course, increased oxidative stress sensitivity and aberrant mitochondrial morphology. Scope of Review: In this review, we focus on the pivotal role of Isc1p in regulating mitochondrial function via SL metabolism, and on Sch9p as central signal transducer. Sch9p is one of the main effectors of the target of rapamycin complex 1 (TORC1), which is regarded as a crucial signaling axis for regulation of Isc1p-mediated events. Finally, we describe the retrograde response, a signaling event originating from dysfunctional mitochondria to the nucleus that results in the induction of nuclear target genes. Intriguingly, the retrograde response is associated with the induction of SL biosynthetic genes. Major Conclusions: All the above suggests a pivotal signaling role for SLs in maintaining correct mitochondrial function in budding yeast. General Significance: Studies with budding yeast provide insight on SL signaling events that affect mitochondrial function.status: publishe