title: Activation of the Hog1p kinase in Isc1p-deficient yeast cells is associated with mitochondrial dysfunction, oxidative stress sensitivity and premature aging.
abstract: The Saccharomyces cerevisiae Isc1p, an orthologue of mammalian neutral sphingomyelinase 2, plays a key role in mitochondrial function, oxidative stress resistance and chronological lifespan. Isc1p functions upstream of the ceramide-activated protein phosphatase Sit4p through the modulation of ceramide levels. Here, we show that both ceramide and loss of Isc1p lead to the activation of Hog1p, the MAPK of the high osmolarity glycerol (HOG) pathway that is functionally related to mammalian p38 and JNK. The hydrogen peroxide sensitivity and premature aging of isc1Δ cells was partially suppressed by HOG1 deletion. Notably, Hog1p activation mediated the mitochondrial dysfunction and catalase A deficiency associated with oxidative stress sensitivity and premature aging of isc1Δ cells. Downstream of Hog1p, Isc1p deficiency activated the cell wall integrity (CWI) pathway. Deletion of the SLT2 gene, which encodes for the MAPK of the CWI pathway, was lethal in isc1Δ cells and this mutant strain was hypersensitive to cell wall stress. However, the phenotypes of isc1Δ cells were not associated with cell wall defects. Our findings support a role for Hog1p in the regulation of mitochondrial function and suggest that constitutive activation of Hog1p is deleterious for isc1Δ cells under oxidative stress conditions and during chronological aging.
authors.affiliation: IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
authors.forename: António Daniel
authors.initials: AD
authors.lastname: Barbosa
authors.forename: João
authors.initials: J
authors.lastname: Graça
authors.forename: Vanda
authors.initials: V
authors.lastname: Mendes
authors.forename: Susana Rodrigues
authors.initials: SR
authors.lastname: Chaves
authors.forename: Maria Amélia
authors.initials: MA
authors.lastname: Amorim
authors.forename: Marta Vaz
authors.initials: MV
authors.lastname: Mendes
authors.forename: Pedro
authors.initials: P
authors.lastname: Moradas-Ferreira
authors.forename: Manuela
authors.initials: M
authors.lastname: Côrte-Real
authors.forename: Vítor
authors.initials: V
authors.lastname: Costa
mesh_terms: D002374:Catalase / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D006861:Hydrogen Peroxide / Q000009:adverse effects; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics*
chemical_list: D002518:Ceramides; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; D002374:Catalase; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; C419391:ISC1 protein, S cerevisiae; D010738:Type C Phospholipases