Sphingolipids and mitochondrial function in budding yeast

Abstract

Background Sphingolipids (Sls) are not only 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 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 mitochondria to the nucleus which results in the induction of nuclear target genes. Intriguingly, the retrograde response also interacts with SL homeostasis. 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.

Proteome and metabolome profiling of wild-type and YCA1 -knock-out yeast cells during acetic acid-induced programmed cell death

“…Therefore, several sphingolipid species control mitochondrial PCD pathway in yeast as well as in mammals [53]. Mitochondrial fission was shown here to occur both en route to YCA1-dependent and YCA1-independent AA-PCD pathways (Fig.…”

“…Yeast has been successfully used as a model system to elucidate several aspects of apoptosis regulation in mammalian cells, particularly of the intrinsic mitochondrial pathway [2,53,[58][59][60].One of the major functions of mitochondria in mammalian apoptosis is the release of cyt c to activate the caspase cascade through apoptosome formation [61]. With this respect yeast metacaspase-encoding gene YCA1 has been shown to be a positive regulator of yeast PCD induced by different stimuli [62], including acetic acid [13].…”

“…In yeast, like in mammalian cells, ceramide levels increase in response to diverse stress treatment [73,74] and the formation of ceramide channels has been proposed as another mechanism mediating the release of pro-apoptotic proteins from mitochondria during the apoptosis [53,75,76]. Therefore, several sphingolipid species control mitochondrial PCD pathway in yeast as well as in mammals [53].…”

“…Since long-chain fatty acids are precursors of sphyngolipids ( Fig. 6 B) which also play an important role as signalling molecules in the regulation of PCD [53], a lipidomic analysis was performed in yca1 control and AA-PCDyca1 cells. The results revealed that several sphingolipid species increased in yca1 cells undergoing AA-PCD (Fig.…”

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…Metabolic changes observed in AD patients and AD models include glucose breakdown and pyruvate oxidation [79], impairment of protein synthesis in early-stage AD [80], increased levels of some amino acids, serotonin, catecholamine and Krebs cycle metabolites [79,81,82], alterations in purine metabolic pathways [79,81], imbalanced cholesterol [83] and sphingolipid [84] homeostasis, large networkwide disruptions in ceramide and phosphoinositide biosynthesis and signaling [85], disruptions in the cellular systems for handling (uptake, intracellular transport, protein loading and storage) transition metals [86,87], dysregulated one-carbon metabolism [88] and some others.…”