Perturbation of sphingolipid metabolism induces endoplasmic reticulum stress-mediated mitochondrial apoptosis in budding yeast.
Sphingolipids are a class of membrane lipids conserved from yeast to mammals which determine whether a cell dies or survives. Perturbations in sphingolipid metabolism cause apoptotic cell death. Recent studies indicate that reduced sphingolipid levels trigger the cell death, but little is known about the mechanisms. In the budding yeast Saccharomyces cerevisiae, we show that reduction in complex sphingolipid levels causes loss of viability, most likely due to the induction of mitochondria-dependent apoptotic cell death pathway, accompanied by changes in mitochondrial and endoplasmic reticulum morphology and endoplasmic reticulum stress. Elevated cytosolic free calcium is required for the loss of viability. These results indicate that complex sphingolipids are essential for maintaining endoplasmic reticulum homeostasis and suggest that perturbation in complex sphingolipid levels activates an endoplasmic reticulum stress-mediated and calcium-dependent pathway to propagate apoptotic signals to the mitochondria.
Department of Bioresource Science and Technology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8528, Japan.
Kentaro
K
Kajiwara
Tetsuya
T
Muneoka
Yu
Y
Watanabe
Takefumi
T
Karashima
Hiroshi
H
Kitagaki
Kouichi
K
Funato
D000935:Antifungal Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006706:Homeostasis; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004718:Saccharomycetales / Q000187:drug effects / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism / Q000494:pharmacology*
D000935:Antifungal Agents; D047630:Depsipeptides; D005656:Fungal Proteins; D013107:Sphingolipids; C071398:aureobasidin A; D002118:Calcium