Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects.
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.


CONCLUSIONS
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.
Department Chemie, Lehrstuhl für Biotechnologie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. katharina.papsdorf@tum.de.
Katharina
K
Papsdorf
Department Chemie, Fachgebiet Elektronenmikroskopie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. christoph.kaiser@tum.de.
Christoph J O
CJ
Kaiser
Department Chemie, Lehrstuhl für Biotechnologie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. adrian.drazic@tum.de.
Adrian
A
Drazic
Biological and Organometallic Laboratories, King Abdullah University of Science and Technology, Thuwal, 23955-6900, Kingdom of Saudi Arabia. stefan.grotzinger@kaust.edu.sa.
Stefan W
SW
Grötzinger
Department Chemie, Fachgebiet Anorganische Chemie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. carmen.haessner@tum.de.
Carmen
C
Haeßner
Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. wolfgang.eisenreich@tum.de.
Wolfgang
W
Eisenreich
Department Chemie, Lehrstuhl für Biotechnologie, Technische Universität München, Lichtenbergstraße 4, 85748, Garching, Germany. klaus.richter@richterlab.de.
Klaus
K
Richter
D000154:Aconitate Hydratase / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D050259:Genes, Mitochondrial; D006706:Homeostasis / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000633:toxicity*; D010710:Phosphates / Q000378:metabolism; D011122:Polyphosphates / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015854:Up-Regulation / Q000187:drug effects
D010455:Peptides; D010710:Phosphates; D011122:Polyphosphates; D029701:Saccharomyces cerevisiae Proteins; C097188:polyglutamine; D002244:Carbon; D007501:Iron; D000154:Aconitate Hydratase