Activation of the Hog1p kinase in Isc1p-deficient yeast cells is associated with mitochondrial dysfunction, oxidative stress sensitivity and premature aging

• Published in: Mechanisms of ageing and development 2012-05, Vol.133 (5), p.317-330
• Main Authors: Barbosa, António Daniel, Graça, João, Mendes, Vanda, Chaves, Susana Rodrigues, Amorim, Maria Amélia, Mendes, Marta Vaz, Moradas-Ferreira, Pedro, Côrte-Real, Manuela, Costa, Vítor
• Format: Article
• Language: English
• Subjects: Aging; c-Jun amino-terminal kinase; Catalase; Catalase - metabolism; Cell Wall - metabolism; Cell walls; Ceramide; Ceramides - metabolism; Chronological aging; Gene Deletion; Gene Expression Regulation, Fungal - genetics; Glycerol; Hog1 protein; Hog1p; Hydrogen peroxide; Hydrogen Peroxide - adverse effects; Isc1p; Life span; MAP kinase; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; osmolarity; Oxidative stress; Oxidative Stress - genetics; Oxidative Stress - physiology; protein phosphatase; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Type C Phospholipases - genetics
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2012.03.007

► Hog1p is activated by ceramide. ► Hyperactivation of Hog1p is associated with premature aging of isc1Δ cells. ► HOG1 deletion restores mitochondrial function of isc1Δ cells. ► Downstream of Hog1p, Isc1p deficiency activates the cell wall integrity (CWI) pathway. ► The phenotypes of isc1Δ cells are not associated with cell wall defects. 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.