Peroxisome Senescence in Human Fibroblasts

Legakis, Julie E.; Koepke, Jay I.; Jedeszko, Chris; Barlaskar, Ferdous; Terlecky, Laura J.; Edwards, Holly; Walton, Paul A.; Terlecky, Stanley R.

doi:10.1091/mbc.e02-06-0322

Cited by 157 publications

(203 citation statements)

References 43 publications

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“…The ⌬ctl-2 mutant of C. elegans represents a convenient model not only for the study of aging but possibly also for the study of the human diseases acatalasemia and hypocatalasemia (23,43,44). Our results support and extend recent findings that peroxisomes not only have important roles in cell metabolism but also are involved in the developmental processes of eukaryotic organisms (23,43,25). …”

Section: Discussionsupporting

confidence: 86%

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans

Petriv¹,

Rachubinski

2004

Journal of Biological Chemistry

136

100

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Studies using the nematode Caenorhabditis elegans as a model system to investigate the aging process have implicated the insulin/insulin-like growth factor-I signaling pathway in the regulation of organismal longevity through its action on a subset of target genes. These targets can be classified into genes that shorten or extend life-span upon their induction. Genes that shorten life-span include a variety of stress response genes, among them genes encoding catalases; however, no evidence directly implicates catalases in the aging process of nematodes or other organisms. Using genetic mutants, we show that lack of peroxisomal catalase CTL-2 causes a progeric phenotype in C. elegans. Lack of peroxisomal catalase also affects the developmental program of C. elegans, since ⌬ctl-2 mutants exhibit decreased egg laying capacity. In contrast, lack of cytosolic catalase CTL-1 has no effect on either nematode aging or egg laying capacity. The ⌬ctl-2 mutation also shortens the maximum life-span of the long lived ⌬clk-1 mutant and accelerates the onset of its egg laying period. The more rapid aging of ⌬ctl-2 worms is apparently not due to increased carbonylation of the major C. elegans proteins, although altered peroxisome morphology in the ⌬ctl-2 mutant suggests that changes in peroxisomal function, including increased production of reactive oxygen species, underlie the progeric phenotype of the ⌬ctl-2 mutant. Our findings support an important role for peroxisomal catalase in both the development and aging of C. elegans and suggest the utility of the ⌬ctl-2 mutant as a convenient model for the study of aging and the human diseases acatalasemia and hypocatalasemia.

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Section: Discussionsupporting

confidence: 86%

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans

Petriv¹,

Rachubinski

2004

Journal of Biological Chemistry

136

100

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“…Peroxisomes, oxidative stress, and inflammation marker enzyme, catalase. However, conditions exist in which the balance of hydrogen peroxide production is upset, and the potentially toxic metabolite accumulates [3][4][5][6][7] . As discussed further below, such phenomena set cells on a pro-aging program with potentially important health ramifications [2] .…”

Section: Topic Highlightmentioning

confidence: 99%

“…In recent years, several circumstances have been described in which the balance is upset and peroxisomes begin to produce excess hydrogen peroxide and related downstream reactive oxygen species. These include certain disease states in which catalase is either not produced or is unstable [15][16][17] , as well as situations in which the enzyme is inactivated [7] or mislocalized [3,18] . Certain xenobiotics/environmental toxins appear to be able to inhibit activity of the enzyme, and aging cells are progressively less able to correctly compartmentalize the critical antioxidant enzyme.…”

Section: Redox Balancementioning

confidence: 99%

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Peroxisomes, oxidative stress, and inflammation

Terlecky

Terlecky²,

Giordano³

2012

WJBC

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Peroxisomes are intracellular organelles mediating a wide variety of biosynthetic and biodegradative reactions. Included among these are the metabolism of hydrogen peroxide and other reactive species, molecules whose levels help define the oxidative state of cells. Loss of oxidative equilibrium in cells of tissues and organs potentiates inflammatory responses which can ultimately trigger human disease. The goal of this article is to review evidence for connections between peroxisome function, oxidative stress, and inflammation in the context of human health and degenerative disease. Dysregulated points in this nexus are identified and potential remedial approaches are presented.

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“…However, we observed in rare cases that eGFP-SKL was localized in the peroxisome, whereas catalase was cytosolic (data not shown). This is most likely due to the fact that the peroxisomal targeting signal (KANL) of catalase is less efficient than the SKL 20,21 Consequently, import of catalase seems to be more sensitive to the peroxisomal defect. Overall, we identified unambiguous mutations in six different PEX genes in 87 ZSS patients (Table 1) using this approach.…”

Section: Complementation Analysis Through Transfectionmentioning

confidence: 99%

Rational diagnostic strategy for Zellweger syndrome spectrum patients

2009

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Zellweger syndrome spectrum (ZSS) comprises a clinically and genetically heterogeneous disease entity, which is caused by mutations in any of the 12 different human PEX genes leading to impaired biogenesis of the peroxisome. Patients potentially suffering from ZSS are diagnosed biochemically by measuring elevated levels of very long chain fatty acids, pristanic acid and phytanic acid in plasma and serum and reduced levels of ether phospholipids in erythrocytes. Published reports on diagnostic procedures for ZSS patients are restricted either to biochemical markers or to defined mutations in a subset of PEX genes. Clarification of the primary genetic defect in an affected patient is crucial for genetic counselling, carrier testing or prenatal diagnosis. In this study, we present a rational diagnostic strategy for patients suspected of ZSS. By combining cell biology and molecular genetic methods in an appropriate sequence, we were able to detect the underlying mutation in various PEX genes within adequate time and cost. We applied this method on 90 patients who presented at our institute, Department of Pediatrics and Pediatric Neurology at Georg August University, and detected 174 mutant alleles within six different PEX genes, including two novel deletions and three new missense mutations in PEX6. Furthermore, this strategy will extend our knowledge on genotype -phenotype correlation in various PEX genes. It will contribute to a better understanding of ZSS pathogenesis, allowing the investigation of the effects of diverse mutations on the interaction between PEX proteins and peroxisomal function in vivo.

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Peroxisome Senescence in Human Fibroblasts

Cited by 157 publications

References 43 publications

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans

Peroxisomes, oxidative stress, and inflammation

Rational diagnostic strategy for Zellweger syndrome spectrum patients

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