Suppression of polyglutamine-induced cytotoxicity in Saccharomyces cerevisiae by enhancement of mitochondrial biogenesis.
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.
Ocampo
Alejandro
A
Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, 1600 NW 10th Ave., Miami, FL 33136, USA.
Zambrano
Andrea
A
Barrientos
Antoni
A
D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009995:Osmosis; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D023081:CCAAT-Binding Factor; C061437:HAP4 protein, S cerevisiae; D024101:Mitochondrial Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; C097188:polyglutamine