Suppression of polyglutamine-induced cytotoxicity in Saccharomyces cerevisiae by enhancement of mitochondrial biogenesis.

Details

Serval ID
serval:BIB_D27CC473FBAE
Type
Article: article from journal or magazin.
Collection
Publications
Title
Suppression of polyglutamine-induced cytotoxicity in Saccharomyces cerevisiae by enhancement of mitochondrial biogenesis.
Journal
FASEB journal
Author(s)
Ocampo A., Zambrano A., Barrientos A.
ISSN
1530-6860 (Electronic)
ISSN-L
0892-6638
Publication state
Published
Issued date
05/2010
Peer-reviewed
Oui
Volume
24
Number
5
Pages
1431-1441
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Alterations in mitochondrial metabolism have been associated with age-related neurodegenerative disorders. This is seen in diseases caused by misfolding of proteins with expanded polyglutamine (polyQ) tracts, such as Huntington's disease. Although evidence of mitochondrial impairment has been extensively documented in patients and disease models, the mechanisms involved and their relevance to the initiation of polyQ cytotoxicity and development of clinical manifestations remain controversial. We report that in yeast models of polyQ cytotoxicity, wild-type and mutant polyQ domains might associate early with the outer mitochondrial membrane. The association of mutant domains with mitochondrial membranes could contribute to induce significant changes in mitochondrial physiology, ultimately compromising the cell's ability to respire. The respiratory defect can be fully prevented by enhancing mitochondrial biogenesis by overexpression of Hap4p, the catalytic subunit of the transcriptional activator Hap2/3/4/5p complex, the master regulator of the expression of many nuclear genes encoding mitochondrial proteins in yeast. Protecting cellular respiratory capacity in this way ameliorates the effect of expanded polyQ on cellular fitness. We conclude that mitochondrial dysfunction is an important contributor to polyQ cytotoxicity. Our results suggest that therapeutic approaches enhancing mitochondrial biogenesis could reduce polyQ toxicity and delay the development of clinical symptoms in patients.
Keywords
CCAAT-Binding Factor/genetics, CCAAT-Binding Factor/metabolism, Humans, Huntington Disease/genetics, Huntington Disease/metabolism, Mitochondria/genetics, Mitochondria/metabolism, Mitochondrial Proteins/biosynthesis, Osmosis, Peptides/genetics, Peptides/metabolism, Saccharomyces cerevisiae/genetics, Saccharomyces cerevisiae/metabolism, Saccharomyces cerevisiae Proteins/genetics, Saccharomyces cerevisiae Proteins/metabolism
Pubmed
Web of science
Create date
14/08/2018 9:50
Last modification date
20/08/2019 15:52
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