title: Sphingolipid signalling mediates mitochondrial dysfunctions and reduced chronological lifespan in the yeast model of Niemann-Pick type C1.
abstract: The Niemann-Pick type C is a rare metabolic disease with a severe neurodegenerative phenotype characterized by an accumulation of high amounts of lipids (cholesterol and sphingolipids) in the late endosomal/lysosomal network. It is caused by loss-of-function point mutations in either NPC1 or NPC2, which seem to mediate proper intracellular lipid transport through endocytic pathway. In this study, we show that yeast cells lacking Ncr1p, an orthologue of mammalian NPC1, exhibited a higher sensitivity to hydrogen peroxide and a shortened chronological lifespan. These phenotypes were associated with increased levels of oxidative stress markers, decreased levels of antioxidant defences and mitochondrial dysfunctions. Moreover, we report that Ncr1p-deficient cells displayed high levels of long chain bases (LCB), and that Sch9p-phospho-T570 and Sch9p levels increased in ncr1Δ cells through a mechanism regulated by Pkh1p, a LCB-activated protein kinase. Notably, deletion of PKH1 or SCH9 suppressed ncr1Δ phenotypes but downregulation of de novo sphingolipid biosynthesis had no protective effect, suggesting that LCBs accumulation may result from an increased turnover of complex sphingolipids. These results suggest that sphingolipid signalling through Pkh1p-Sch9p mediate mitochondrial dysfunction, oxidative stress sensitivity and shortened chronological lifespan in the yeast model of Niemann-Pick type C disease.
authors.affiliation: IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal; ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Vilaça
authors.forename: Elísio
authors.initials: E
authors.lastname: Silva
authors.forename: André
authors.initials: A
authors.lastname: Nadais
authors.forename: Vítor
authors.initials: V
authors.lastname: Teixeira
authors.forename: Nabil
authors.initials: N
authors.lastname: Matmati
authors.forename: Joana
authors.initials: J
authors.lastname: Gaifem
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Sá Miranda
authors.forename: Vítor
authors.initials: V
authors.lastname: Costa
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D017353:Gene Deletion; D008928:Mitochondria / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C490168:NCR1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D033921:Vesicular Transport Proteins; D064413:3-Phosphoinositide-Dependent Protein Kinases; C118385:PKH1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C530964:SCH9 protein, S cerevisiae