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TitleIsc1p plays a key role in hydrogen peroxide resistance and chronological lifespan through modulation of iron levels and apoptosis
Author(s)Almeida, Teresa
Marques, Marta
Mojzita, Dominik
Amorim, Maria A.
Silva, Rui Filipe Duarte
Almeida, Bruno Miguel Barroso Rodrigues
Rodrigues, Pedro
Ludovico, Paula
Hohmann, Stefan
Moradas-Ferreira, Pedro
Côrte-Real, Manuela
Costa, Vítor
Gene Expression Profiling
Gene Expression Regulation, Fungal
Hydrogen Peroxide
Intracellular Space
Models, Biological
Oligonucleotide Array Sequence Analysis
Oxidative Stress
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Time Factors
Type C Phospholipases
Issue dateMar-2008
PublisherAmerican Society for Cell Biology
JournalMolecular Biology of the Cell
Abstract(s)The inositolphosphosphingolipid phospholipase C (Isc1p) of Saccharomyces cerevisiae belongs to the family of neutral sphingomyelinases that generates the bioactive sphingolipid ceramide. In this work the role of Isc1p in oxidative stress resistance and chronological lifespan was investigated. Loss of Isc1p resulted in a higher sensitivity to hydrogen peroxide that was associated with an increase in oxidative stress markers, namely intracellular oxidation, protein carbonylation, and lipid peroxidation. Microarray analysis showed that Isc1p deficiency up-regulated the iron regulon leading to increased levels of iron, which is known to catalyze the production of the highly reactive hydroxyl radicals via the Fenton reaction. In agreement, iron chelation suppressed hydrogen peroxide sensitivity of isc1Delta mutants. Cells lacking Isc1p also displayed a shortened chronological lifespan associated with oxidative stress markers and aging of parental cells was correlated with a decrease in Isc1p activity. The analysis of DNA fragmentation and caspase-like activity showed that Isc1p deficiency increased apoptotic cell death associated with oxidative stress and aging. Furthermore, deletion of Yca1p metacaspase suppressed the oxidative stress sensitivity and premature aging phenotypes of isc1Delta mutants. These results indicate that Isc1p plays an important role in the regulation of cellular redox homeostasis, through modulation of iron levels, and of apoptosis.
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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