Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

BMC Genomics

Research Article

Stefan W. Grötzinger¹  Carmen Haeßner²  Christoph J. O. Kaiser³  Wolfgang Eisenreich⁴  Klaus Richter⁵  Katharina Papsdorf⁵  Adrian Drazic⁵ 

[1] Biological and Organometallic Laboratories, King Abdullah University of Science and Technology, 23955-6900, Thuwal, Kingdom of Saudi Arabia;Department Chemie, Fachgebiet Anorganische Chemie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany;Department Chemie, Fachgebiet Elektronenmikroskopie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany;Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany;Department Chemie, Lehrstuhl für Biotechnologie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany;

关键词: Polyglutamine;    Iron-sulfur cluster;    Mitochondria;    Neurodegenerative disease;   

DOI  :  10.1186/s12864-015-1831-7

 received in 2015-03-10, accepted in 2015-08-07,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundProtein 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.ResultsTo 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.ConclusionThese 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.

【 授权许可】

CC BY   
© Papsdorf et al. 2015