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

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• 作者：Ant&oacute ; nio Daniel Barbosa^a ; ^b ; Joã ; o Graç ; a^a ; Vanda Mendes^a ; Susana Rodrigues Chaves^c ; Maria Amé ; lia Amorim^a ; ^b ; Marta Vaz Mendes^a ; Pedro Moradas-Ferreira^a ; ^b ; Manuela Cô ; rte-Real^c ; Ví ; tor Costa^a ; ^b ; ^{vcosta@ibmc.up.pt}
• 关键词：CLS ; chronological lifespan ; DNPH ; 2 ; 4-dinitrophenylhydrazine ; HOG ; high osmolarity glycerol ; CWI ; cell wall integrity ; MAPK ; mitogen-activated protein kinase ; H2DCFDA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate ; ROS ; reactive oxygen species
• 刊名：Mechanisms of Ageing and Development
• 出版年：2012
• 期刊代码：193_00476374
• 类别：med
• 出版时间：May, 2012
• 卷：133
• 期：5
• 页码：317-330
• 文件大小：1480 K

摘要

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 isc1螖 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 isc1螖 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 isc1螖 cells and this mutant strain was hypersensitive to cell wall stress. However, the phenotypes of isc1螖 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 isc1螖 cells under oxidative stress conditions and during chronological aging.