Hydrogen peroxide scavenging rescues frataxin deficiency in a
            <i>Drosophila</i>
            model of Friedreich's ataxia

Anderson, Peter; Kirby, Kim; Orr, William C.; Hilliker, Arthur J.; Phillips, J. P.

doi:10.1073/pnas.0709691105

Cited by 95 publications

(103 citation statements)

References 55 publications

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“…Although it is recognized that the cellular antioxidant defense mechanisms are defective in frataxin-deficient cells, it is not clear which molecules among ROS accumulate and are responsible for the damage. Different studies in yeast, Drosophila and patient fibroblasts suggested that H 2 O 2 could be the accumulating species [7,16,24]. In agreement with this, yeast Dyfh1 cells are extremely sensitive to H 2 O 2 .…”

Section: Discussionsupporting

confidence: 63%

The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

Lefevre¹,

Sliwa²,

Auchère³

et al. 2011

FEBS Letters

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Edited by Vladimir SkulachevKeywords: Frataxin Friedreich ataxia Metacaspase Oxidative stress Yca1 a b s t r a c t Friedreich ataxia is the most common recessive neurodegenerative disease and is caused by reduced expression of mitochondrial frataxin. Frataxin depletion causes impairment in iron-sulfur cluster and heme biosynthesis, disruption of iron homeostasis and hypersensitivity to oxidants. Currently no pharmacological treatment blocks disease progression, although antioxidant therapies proved to benefit patients. We show that sensitivity of yeast frataxin-deficient cells to hydrogen peroxide is partially mediated by the metacaspase. Metacaspase deletion in frataxin-deficient cells results in recovery of antioxidant capacity and heme synthesis. In addition, our results suggest that metacaspase is associated with mitochondrial respiration, intracellular redox control and genomic stability.

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Section: Discussionsupporting

confidence: 63%

The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

Lefevre¹,

Sliwa²,

Auchère³

et al. 2011

FEBS Letters

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“…When these activities were restored, the activities of several iron-sulfur-containing enzymes were also recovered, suggesting that ironsulfur deficiency in ⌬yfh1 yeasts is due to the lack of SOD activities. In frataxin-deficient Drosophila melanogaster, aconitase deficiency is observed only under hyperoxia conditions (19), whereas H 2 O 2 scavenging restores aconitase activity (20). All of these observations suggest that lack of iron-sulfur enzymatic activities in frataxin-deficient cells could be a consequence of oxidative stress conditions generated by iron accumulation.…”

mentioning

confidence: 71%

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Moreno-Cermeño

Òbis

Bellı́

et al. 2010

Journal of Biological Chemistry

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The primary function of frataxin, a mitochondrial protein involved in iron homeostasis, remains controversial. Using a yeast model of conditional expression of the frataxin homologue YFH1, we analyzed the primary effects of YFH1 depletion. The main conclusion unambiguously points to the upregulation of iron transport systems as a primary effect of YFH1 down-regulation. We observed that inactivation of aconitase, an iron-sulfur enzyme, occurs long after the iron uptake system has been activated. Decreased aconitase activity should be considered part of a group of secondary events promoted by iron overloading, which includes decreased superoxide dismutase activity and increased protein carbonyl formation. Impaired manganese uptake, which contributes to superoxide dismutase deficiency, has also been observed in YFH1-deficient cells. This low manganese content can be attributed to the down-regulation of the metal ion transporter Smf2. Low Smf2 levels were not observed in AFT1/YFH1 double mutants, indicating that high iron levels could be responsible for the Smf2 decline. In summary, the results presented here indicate that decreased iron-sulfur enzyme activities in YFH1-deficient cells are the consequence of the oxidative stress conditions suffered by these cells.

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“…In Drosophila, overexpression of Jafrac1 has been shown to counteract the enhanced susceptibility of immune-regulated catalase knockdown flies to natural infections (14). Moreover, mitochondrial peroxiredoxin (Dpx-5037, mTPx) has been reported to restore wild-type life span in a Drosophila model for Friedreich's ataxia (27).…”

Section: Discussionmentioning

confidence: 99%

JNK/FOXO-mediated Neuronal Expression of Fly Homologue of Peroxiredoxin II Reduces Oxidative Stress and Extends Life Span

Lee

Iijima-Ando

Iijima

et al. 2009

Journal of Biological Chemistry

122

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Activation of c-Jun N-terminal kinase (JNK) signaling in neurons increases stress resistance and extends life span, in part through FOXO-mediated transcription in Drosophila. However, the JNK/ FOXO target genes are unknown. Here, we identified Jafrac1, a Drosophila homolog of human Peroxiredoxin II (hPrxII), as a downstream effecter of JNK/FOXO signaling in neurons that enhances stress resistance and extends life span. We found that Jafrac1 was expressed in the adult brain and induced by paraquat, a reactive oxygen species-generating chemical. RNA interference-mediated neuronal knockdown of Jafrac1 enhanced, while neuronal overexpression of Jafrac1 and hPrxII suppressed, paraquat-induced lethality in flies. Neuronal expression of Jafrac1 also significantly reduced ROS levels, restored mitochondrial function, and attenuated JNK activation caused by paraquat. Activation of JNK/FOXO signaling in neurons increased the Jafrac1 expression level under both normal and oxidative stressed conditions. Moreover, neuronal knockdown of Jafrac1 shortened, while overexpression of Jafrac1 and hPrxII extended, the life span in flies. These results support the hypothesis that JNK/FOXO signaling extends life span via amelioration of oxidative damage and mitochondrial dysfunction in neurons.FOXO transcription factors are key regulators of growth, metabolism, life span, and stress resistance in various organisms, including Drosophila (1, 2). FOXO is regulated by the insulin signaling pathway and the stress-induced JNK 4 signaling pathway (3, 4). Oxidative stress activates the stress-responsive JNK, which promotes FOXO nuclear localization and upregulates expression of antioxidant proteins (5, 6).In Drosophila, neuronal activation of JNK/FOXO signaling confers resistance to oxidative stress and extends life span (4, 7). Neurons are particularly susceptible to oxidative damage because of their high levels of ROS production and relatively low levels of antioxidant enzymes (8). Thus, activation of the JNK/FOXO pathway in neurons may extend life span through up-regulation of anti-oxidative stress genes. However, little is known regarding the JNK/FOXO target genes in neurons.Thiol-reducing systems are important reducers of many oxidative stressors, such as peroxide (9). Peroxiredoxin (Prx), also called thioredoxin peroxidase, eliminates hydroperoxide with thioredoxin as an immediate hydrogen donor and reduces ROS levels (10). Among six distinct mammalian Prxs (I-VI), Prx II is exclusively expressed in the brain (11), suggesting that Prx II may play an important role in response to oxidative stress in neurons. However, the regulation of PrxII expression in neurons has not been elucidated. In this study, we demonstrated that neuronal expression of Jafrac1, a Drosophila homologue of human Prx II (hPrxII), was regulated by JNK/FOXO signaling, promoted resistance to oxidative stress, and extended the life span of the flies. EXPERIMENTAL PROCEDURESDrosophila Culture and Mutants-Drosophila melanogaster were kept at 25°C and cultured using standar...

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Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia

Cited by 95 publications

References 55 publications

The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

JNK/FOXO-mediated Neuronal Expression of Fly Homologue of Peroxiredoxin II Reduces Oxidative Stress and Extends Life Span

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