Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects.

Katharina Papsdorf,Christoph J O Kaiser,Klaus Richter,Stefan W Grötzinger,Wolfgang Eisenreich,Carmen Haeßner,Adrian Drazic

doi:10.1186/s12864-015-1831-7

Katharina Papsdorf, Christoph J O Kaiser + Show 5 more

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https://doi.org/10.1186/s12864-015-1831-7

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Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1831-7) contains supplementary material, which is available to authorized users.

Highlights

Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases
Q56-Yellow fluorescent protein (YFP) toxicity is suppressed by a set of mitochondrial genes In order to study Stretch of polyglutamine residues (polyQ) induced toxicity we used a yeast model system, which consists of three different constructs fusing either zero, 30 or 56 glutamine residues to YFP [20]
Toxic and non-toxic polyQ stretches disturb the phosphate balance of the cells To obtain more information on the condition of the pica yeast cells, we investigated the transcriptomic status of Q56-YFP intoxicated yeasts

Summary

Introduction

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. Protein misfolding and aggregation of certain proteins were found to play a major role in a variety of diseases, commonly called proteopathies [1,2,3,4]. For many of these diseases, age is a major risk factor. The age of disease onset and the aggregation propensity of Huntingtin are closely related to the length of a stretch of polyglutamine (polyQ) residues in its N-terminal domain [7]. The phenomenon of polyQ aggregation is not limited to Huntington’s disease, but approximately a dozen other diseases are associated with extended glutamine stretches in specific proteins [9,10,11]

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