Reversion of a long-living, undifferentiated mutant of Podospora anserina by copper

Marbach, Karin; Fernández-Larrea, Juan; Ståhl, Ulf

doi:10.1007/bf00313809

Cited by 29 publications

(29 citation statements)

References 21 publications

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“…A decrease in ferric/cupric reductase and laccase activities was also observed in the melanindeficient oxy2 (copper-sensing transcription factor) mutant and was attributed to the lack of copper (52). Similar observations have been reported in Podospora anserina, wherein the loss of the GRISEA gene caused a melanin-negative phenotype that was repaired by copper supplementation (53,54).…”

Section: Discussionsupporting

confidence: 85%

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

Saikia

Oliveira

et al. 2014

Infect Immun

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Iron acquisition is critical for the ability of the pathogenic yeast Cryptococcus neoformans to cause disease in vertebrate hosts. In particular, iron overload exacerbates cryptococcal disease in an animal model, defects in iron acquisition attenuate virulence, and iron availability influences the expression of major virulence factors. C. neoformans acquires iron by multiple mechanisms, including a ferroxidase-permease high-affinity system, siderophore uptake, and utilization of both heme and transferrin. In this study, we examined the expression of eight candidate ferric reductase genes and their contributions to iron acquisition as well as to ferric and cupric reductase activities. We found that loss of the FRE4 gene resulted in a defect in production of the virulence factor melanin and increased susceptibility to azole antifungal drugs. In addition, the FRE2 gene was important for growth on the iron sources heme and transferrin, which are relevant for proliferation in the host. Fre2 may participate with the ferroxidase Cfo1 of the high-affinity uptake system for growth on heme, because a mutant lacking both genes showed a more pronounced growth defect than the fre2 single mutant. A role for Fre2 in iron acquisition is consistent with the attenuation of virulence observed for the fre2 mutant. This mutant also was defective in accumulation in the brains of infected mice, a phenotype previously observed for mutants with defects in high-affinity iron uptake (e.g., the cfo1 mutant). Overall, this study provides a more detailed view of the iron acquisition components required for C. neoformans to cause cryptococcosis.

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Section: Discussionsupporting

confidence: 85%

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

Saikia

Oliveira

et al. 2014

Infect Immun

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“…This is not in concordance with a direct role of the active copper-modulated transcription factor GRISEA in bringing life to an end, as it may be concluded from the demonstration that Grisea is not expressed in the long-lived lossof-function mutant grisea. The data presented in this work underscore the significant role of cellular copper, which has also been suggested by previous mutant rescue experiments (8,33).…”

Section: Discussionsupporting

confidence: 85%

“…In the corresponding mutant grisea, a high-affinity copper transporter gene is not expressed (unpublished data), consequently leading to decreased cellular copper levels. The phenotype of the mutant can be rescued to wild-type characteristics by growing cultures in medium containing high amounts of copper, most likely due to the uptake of copper via a low-affinity system (7,33). These data clearly indicate an important effect of copper on the lifespan of P. anserina.…”

Section: Resultsmentioning

confidence: 78%

Copper-Modulated Gene Expression and Senescence in the Filamentous Fungus Podospora anserina

Borghouts

Werner

Elthon

et al. 2001

Molecular and Cellular Biology

110

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We have previously shown that the control of cellular copper homeostasis by the copper-modulated transcription factor GRISEA has an important impact on the phenotype and lifespan of Podospora anserina. Here we demonstrate that copper depletion leads to the induction of an alternative respiratory pathway and to an increase in lifespan. This response compensates mitochondrial dysfunctions via the expression of PaAox, a nuclear gene coding for an alternative oxidase. It resembles the retrograde response in Saccharomyces cerevisiae. In P. anserina, this pathway appears to be induced by specific impairments of the copper-dependent cytochrome c oxidase. It is not induced as the result of a general decline of mitochondrial functions during senescence. We cloned and characterized PaAox. Transcript levels are decreased when cellular copper, superoxide, and hydrogen peroxide levels are raised. Copper also controls transcript levels of PaSod2, the gene encoding the mitochondrial manganese superoxide dismutase (PaSOD2). PaSod2 is a target of transcription factor GRISEA. During the senescence of wild-type strain s, the activity of PaSOD2 decreases, whereas the activity of the cytoplasmic copper/zinc superoxide dismutase (PaSOD1) increases. Collectively, the data explain the postponed senescence of mutant grisea as a defined consequence of copper depletion, ultimately leading to a reduction of oxidative stress. Moreover, they suggest that during senescence of the wild-type strain, copper is released from mitochondria. The involved mechanism is unknown. However, it is striking that the permeability of mitochondrial membranes in animal systems changes during apoptosis and that mitochondrial proteins with an important impact on this type of cellular death are released.

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“…To verify this assumption, we analyzed total RNA from the wild-type of P. anserina, from the long-lived mutant, from a transformant in which the mutant phenotype was complemented by the introduction of the cloned wild-type copy of grisea, and from a mutant strain grown in the presence of additional copper. The latter analysis was performed because it was shown earlier that additional copper in the medium rescues the mutant phenotype (35). cDNA of the different strains was synthesized by using an oligo(dT) primer.…”

Section: Resultsmentioning

confidence: 99%

“…The relevance of oxidative stress and the free radical theory of aging (46) for P. anserina is supported by the observation that grisea codes for a transcription factor that appears to be involved in a tight regulation of cellular copper levels and the fact that the phenotype of grisea can be rescued by additional copper in the growth medium (35). The increased life span of the mutant strain may be explained by a reduction in the formation of reactive oxygene species (ROS).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA rearrangements of Podospora anserina are under the control of the nuclear gene grisea

Borghouts

Kimpel²,

Osiewacz³

1997

Proc. Natl. Acad. Sci. U.S.A.

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Podospora anserina is a filamentous fungus with a limited life span. Life span is controlled by nuclear and extranuclear genetic traits. Herein we report the nature of four alterations in the nuclear gene grisea that lead to an altered morphology, a defect in the formation of female gametangia, and an increased life span. Three sequence changes are located in the 5 upstream region of the grisea ORF. One mutation is a G 3 A transition at the 5 splice site of the single intron of the gene, leading to a RNA splicing defect. This loss-of-function affects the amplification of the first intron of the mitochondrial cytochrome c oxidase subunit I gene (COI) and the specific mitochondrial DNA rearrangements that occur during senescence of wild-type strains. Our results indicate that the nuclear gene grisea is part of a molecular machinery involved in the control of mitochondrial DNA reorganizations. These DNA instabilities accelerate but are not a prerequisite for the aging of P. anserina cultures.Aging of biological systems, as the progressive functional impairment of living beings leading to an increase in agerelated mortality, is a complex process that is dependent on both environmental and genetic factors. With regard to the genetic basis, instabilities of the mitochondrial DNA (mtDNA) were reported in various organisms to be involved in aging leading to mitochondrial dysfunction and degeneration (for reviews, see refs. 1 and 2). Moreover, increased instabilities of the mtDNA were found to lead to premature degeneration processes. Examples of this type are premature death syndromes in fungi and various neuromuscular diseases in humans (for reviews, see refs. 3-5). Interestingly, in some cases, these syndromes are due to the mutation of a nuclear gene that demonstrate that the integrity of the mtDNA is under the control of nuclear factors (6-10). Unfortunately, until now, the molecular mechanisms involved in this maintenance function have not been elucidated in any case.In the filamentous fungus Podospora anserina, all wildstrains are characterized by a limited life span. After prolonged vegetative growth, they display various symptoms of senescence. Since the first description of this syndrome (11), it has become clear that nuclear-mitochondrial interactions are crucially involved in its control (for reviews, see refs. 12-15). Detailed molecular investigations revealed that gross reorganizations of the mtDNA occur during senescence. These reorganizations are almost quantitative and lead to impairment of the energy-generating system located in mitochondria. Similar processes were subsequently reported to occur in senescing strains of Neurospora (16)(17)(18). In all cases, the activity of mobile genetic elements of circular or linear structure were found to be relevant. More specifically, in P. anserina, it appears that the mobility of a circular plasmid, termed plasmid-like DNA (plDNA) or ␣senDNA (19,20), which is a derivative of the first intron of the cytochrome oxidase gene subunit I (COI), is responsible f...

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Reversion of a long-living, undifferentiated mutant of Podospora anserina by copper

Cited by 29 publications

References 21 publications

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

Copper-Modulated Gene Expression and Senescence in the Filamentous Fungus Podospora anserina

Mitochondrial DNA rearrangements of Podospora anserina are under the control of the nuclear gene grisea

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