Stress-Activated Degradation of Sphingolipids Regulates Mitochondrial Function and Cell Death in Yeast

[EN] Sphingolipids are regulators of mitochondria-mediated cell death in higher eukaryotes. Here, we investigate how changes in sphingolipid metabolism and downstream intermediates of sphingosine impinge on mitochondrial function. We found in yeast that within the sphingolipid degradation pathway, the production via Dpl1p and degradation via Hfd1p of hexadecenal are critical for mitochondrial function and cell death. Genetic interventions, which favor hexadecenal accumulation, diminish oxygen consumption rates and increase reactive oxygen species production and mitochondrial fragmentation and vice versa. The location of the hexadecenal-degrading enzyme Hfd1p in punctuate structures all along the mitochondrial network depends on a functional ERMES (endoplasmic reticulum-mitochondria encounter structure) complex, indicating that modulation of hexadecenal levels at specific ER-mitochondria contact sites might be an important trigger of cell death. This is further supported by the finding that externally added hexadecenal or the absence of Hfd1p enhances cell death caused by ectopic expression of the human Bax protein. Finally, the induction of the sphingolipid degradation pathway upon stress is controlled by the Hog1p MAP kinase. Therefore, the stress-regulated modulation of sphingolipid degradation might be a conserved way to induce cell death in eukaryotic organisms.The authors thank Eulalia de Nadal, William Prinz, Benoit Kornmann, Stephen Manon, Benedikt Westermann, and Frank Madeo for the kind gift of yeast strains and plasmids. The authors thank Alba Calatayud for her help with Bax expression experiments and Benito Alarcon for his help with the confocal microscopy. This work was supported by the grants from the Ministerio de Economia y Competitividad (BFU2011-23326 and BFU2016-75792-R).Manzanares-Estreder, S.; Pascual-Ahuir Giner, MD.; Proft, M. (2017). Stress-Activated Degradation of Sphingolipids Regulates Mitochondrial Function and Cell Death in Yeast. Oxidative Medicine and Cellular Longevity. (2708345):1-15. https://doi.org/10.1155/2017/2708345S115270834