Regulation of Mitochondrial Biogenesis in <i>Saccharomyces cerevisiae</i>

Winde, Johannes H. de; Grivell, Leslie A.

doi:10.1111/j.1432-1033.1995.200_1.x

Cited by 17 publications

(8 citation statements)

References 43 publications

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“…One was the suppressor Hap4, a transcriptional activator of respiratory genes (De Winde and Grivell, 1995). The other, Mks1, enhanced -syn toxicity.…”

Section: Resultsmentioning

confidence: 99%

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models

Auluck

Outeiro

et al. 2010

Disease Models &Amp; Mechanisms

160

199

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SUMMARY α-Synuclein (α-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because α-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We previously created a yeast model of α-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to α-syn expression. We also uncovered a core group of proteins with diverse activities related to α-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of α-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress α-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of α-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced α-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of α-syn foci, re-established ER-to-Golgi trafficking and ameliorated α-syn-mediated damage to mitochondria. They also corrected the toxicity of α-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of α-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.

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“…One was the suppressor Hap4, a transcriptional activator of respiratory genes (De Winde and Grivell, 1995). The other, Mks1, enhanced -syn toxicity.…”

Section: Resultsmentioning

confidence: 99%

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models

Auluck

Outeiro

et al. 2010

Disease Models &Amp; Mechanisms

160

199

View full text Add to dashboard Cite

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“…Furthermore, given the number of proteins which according to our data are neither dependent upon the Snf1 pathway or the Msn2/Msn4 pathway, it remains possible that additional pathways under the control of cAMP participate to the proteome changes. From this point of view, it will be of interest to consider how other transcriptional factors known to play a role in the diauxic shift, such as Adr1 or the Hap2/3/4/5 complex [23,28], can be integrated in these data.…”

Section: Integration Of Data: An Overview Of the Regulatory Network Cmentioning

confidence: 99%

Dissecting regulatory networks by means of two‐dimensional gel electrophoresis: Application to the study of the diauxic shift in the yeast Saccharomyces cerevisiae

Haurie¹,

Sagliocco²,

Boucherie³

2004

Proteomics

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Using a proteomic approach based on the two-dimensional (2-D) gel analysis of synthesized proteins, we investigated the involvement of the Snf1 kinase pathway in the regulation of gene expression during the diauxic shift in Saccharomyces cerevisiae. For this purpose, we used a mutant strain deleted for SNF4, the gene coding for the activator subunit of Snf1p. The levels of synthesis of 82 spots were found to be affected by the absence of Snf4p at the diauxic shift. Half of the proteins which exhibit a reduced synthesis in the mutant strain are proteins whose genes are controlled by the transcriptional activator Cat8p, a target of Snf1p. Proteins with an increased level of synthesis in the mutant strain were also observed. Among them are glycolytic enzymes whose synthesis is strongly reduced when wild-type cells enter the diauxic shift. This observation suggests that Snf1p exerts a negative control on the expression of glycolytic genes during the diauxic transition. The results obtained in this study were compiled with those previously obtained by similar proteomic approach with other regulatory factors involved in the diauxic shift. This compilation illustrates how 2-D gel electrophoresis can be used to elucidate the network of regulators participating to complex biological process.

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“…Under respiratory conditions, a tight regulation is essential, as the kinetic properties of the NADP‐GDH hexamers depend on the proportion of their constituting Gdh1p and Gdh3p monomers. GDH1 regulation is also determined by transcriptional activators that have been considered as exclusive of either nitrogen or carbon metabolism (Gln3p and HAP complex) (Courchesne and Magasanik, 1988; Blinder and Magasanik, 1995; Coffman et al ., 1995; 1996; De Winde and Grivell, 1995; Dang et al ., 1996). These observations led to suggest that a gene such as GDH1 should be modulated by the regulatory networks that determine the metabolism of these two compounds (Dang et al ., 1996; Riego et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

Swi/SNF‐GCN5‐dependent chromatin remodelling determines induced expression of GDH3, one of the paralogous genes responsible for ammonium assimilation and glutamate biosynthesis in Saccharomyces cerevisiae

Avendaño

Riego

DeLuna

et al. 2005

Molecular Microbiology

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SummaryIt is accepted that Saccharomyces cerevisiae genome arose from complete duplication of eight ancestral chromosomes; functionally normal ploidy was recovered because of the massive loss of 90% of duplicated genes. There is evidence that indicates that part of this selective conservation of gene pairs is compelling to yeast facultative metabolism. As an example, the duplicated NADP-glutamate dehydrogenase pathway has been maintained because of the differential expression of the paralogous GDH1 and GDH3 genes, and the biochemical specialization of the enzymes they encode. The present work has been aimed to the understanding of the regulatory mechanisms that modulate GDH3 transcriptional activation. Our results show that GDH3 expression is repressed in glucose-grown cultures, as opposed to what has been observed for GDH1 , and induced under respiratory conditions, or under stationary phase. Although GDH3 pertains to the nitrogen metabolic network, and its expression is Gln3p-regulated, complete derepression is ultimately determined by the carbon source through the action of the SAGA and SWI/SNF chromatin remodelling complexes. GDH3 carbonmediated regulation is over-imposed to that exerted by the nitrogen source, highlighting the fact that operation of facultative metabolism requires strict control of enzymes, like Gdh3p, involved in biosynthetic pathways that use tricarboxylic acid cycle intermediates.

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Regulation of Mitochondrial Biogenesis in Saccharomyces cerevisiae

Cited by 17 publications

References 43 publications

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models

Dissecting regulatory networks by means of two‐dimensional gel electrophoresis: Application to the study of the diauxic shift in the yeast Saccharomyces cerevisiae

Swi/SNF‐GCN5‐dependent chromatin remodelling determines induced expression of GDH3, one of the paralogous genes responsible for ammonium assimilation and glutamate biosynthesis in Saccharomyces cerevisiae

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