Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

Handle URI:
http://hdl.handle.net/10754/576984
Title:
Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects
Authors:
Papsdorf, Katharina; Kaiser, Christoph J. O.; Drazic, Adrian; Grötzinger, Stefan W.; Haeßner, Carmen; Eisenreich, Wolfgang; Richter, Klaus
Abstract:
Background Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. Conclusion These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.
KAUST Department:
Biological and Organometallic Catalysis Laboratories
Citation:
Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects 2015, 16 (1) BMC Genomics
Publisher:
Springer Science + Business Media
Journal:
BMC Genomics
Issue Date:
3-Sep-2015
DOI:
10.1186/s12864-015-1831-7
Type:
Article
ISSN:
1471-2164
Is Supplemented By:
Papsdorf, K., Kaiser, C., Drazic, A., GrĂśtzinger, S., HaeĂ Ner, C., Eisenreich, W., & Richter, K. (2015). Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects. Figshare. https://doi.org/10.6084/m9.figshare.c.3618170; DOI:10.6084/m9.figshare.c.3618170; HANDLE:http://hdl.handle.net/10754/624133
Additional Links:
http://www.biomedcentral.com/1471-2164/16/662
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorPapsdorf, Katharinaen
dc.contributor.authorKaiser, Christoph J. O.en
dc.contributor.authorDrazic, Adrianen
dc.contributor.authorGrötzinger, Stefan W.en
dc.contributor.authorHaeßner, Carmenen
dc.contributor.authorEisenreich, Wolfgangen
dc.contributor.authorRichter, Klausen
dc.date.accessioned2015-09-09T06:14:42Zen
dc.date.available2015-09-09T06:14:42Zen
dc.date.issued2015-09-03en
dc.identifier.citationPolyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects 2015, 16 (1) BMC Genomicsen
dc.identifier.issn1471-2164en
dc.identifier.doi10.1186/s12864-015-1831-7en
dc.identifier.urihttp://hdl.handle.net/10754/576984en
dc.description.abstractBackground Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. Conclusion These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.en
dc.language.isoenen
dc.publisherSpringer Science + Business Mediaen
dc.relation.urlhttp://www.biomedcentral.com/1471-2164/16/662en
dc.rightsOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.subjectPolyglutamineen
dc.subjectIron-sulfur clusteren
dc.subjectMitochondriaen
dc.subjectNeurodegenerative diseaseen
dc.titlePolyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defectsen
dc.typeArticleen
dc.contributor.departmentBiological and Organometallic Catalysis Laboratoriesen
dc.identifier.journalBMC Genomicsen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartment Chemie, Lehrstuhl für Biotechnologie, Technische Universität München, Lichtenbergstraße 4, Garching, 85748, Germanyen
dc.contributor.institutionDepartment Chemie, Fachgebiet Elektronenmikroskopie, Technische Universität München, Lichtenbergstraße 4, Garching, 85748, Germanyen
dc.contributor.institutionDepartment Chemie, Fachgebiet Anorganische Chemie, Technische Universität München, Lichtenbergstraße 4, Garching, 85748, Germanyen
dc.contributor.institutionDepartment Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, Garching, 85748, Germanyen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorGrötzinger, Stefan W.en
dc.relation.isSupplementedByPapsdorf, K., Kaiser, C., Drazic, A., GrĂśtzinger, S., HaeĂ Ner, C., Eisenreich, W., & Richter, K. (2015). Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects. Figshare. https://doi.org/10.6084/m9.figshare.c.3618170en
dc.relation.isSupplementedByDOI:10.6084/m9.figshare.c.3618170en
dc.relation.isSupplementedByHANDLE:http://hdl.handle.net/10754/624133en
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