Knupp, Jeffrey Martínez-Montañés, Fernando Van Den Bergh, Francoise Cottier, Stephanie Schneiter, Roger Beard, Daniel Chang, Amy 2017 Sphingolipids are structural components of cell membranes that have signaling roles to regulate many activities, including mitochondrial function and cell death. Sphingolipid metabolism is integrated with numerous metabolic networks, and dysregulated sphingolipid metabolism is associated with disease. Here, we describe a monogenic yeast model for sphingolipid accumulation. A csg2Δ mutant cannot readily metabolize and accumulates the complex sphingolipid inositol phosphorylceramide (IPC). In these cells, aberrant activation of Ras GTPase is IPC-dependent, and accompanied by increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial mass. Survival or death of csg2Δ cells depends on nutritional status. Abnormal Ras activation in csg2Δ cells is associated with impaired Snf1/AMPK protein kinase, a key regulator of energy homeostasis. csg2Δ cells are rescued from ROS production and death by overexpression of mitochondrial catalase Cta1, abrogation of Ras hyperactivity or genetic activation of Snf1/AMPK. These results suggest that sphingolipid dysregulation compromises metabolic integrity via Ras and Snf1/AMPK pathways. application/pdf https://folia.unifr.ch/global/documents/306452 https://folia.unifr.ch/documents/306452/files/sch_sac.pdf https://folia.unifr.ch/documents/306452/files/sch_sac_sm.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/cdd.2017.128 info:eu-repo/semantics/openAccess License undefined Cell Death and Differentiation. - 2017, vol. 24, no. 12, p. 2044 info:eu-repo/classification/udc/57 Sphingolipid accumulation causes mitochondrial dysregulation and cell death http://purl.org/coar/resource_type/c_6501