Suppression of polyglutamine-induced cytotoxicity in Saccharomyces cerevisiae by enhancement of mitochondrial biogenesis. 2010

Alejandro Ocampo, and Andrea Zambrano, and Antoni Barrientos
Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, 1600 NW 10th Ave., Miami, FL 33136, USA.

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.

UI MeSH Term Description Entries
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D009995 Osmosis Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. Osmoses
D010455 Peptides Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS. Peptide,Polypeptide,Polypeptides
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006816 Huntington Disease A familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive CHOREA and DEMENTIA in the fourth or fifth decade of life. Common initial manifestations include paranoia; poor impulse control; DEPRESSION; HALLUCINATIONS; and DELUSIONS. Eventually intellectual impairment; loss of fine motor control; ATHETOSIS; and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. The juvenile variant has a more fulminant course including SEIZURES; ATAXIA; dementia; and chorea. (From Adams et al., Principles of Neurology, 6th ed, pp1060-4) Huntington Chorea,Juvenile Huntington Disease,Akinetic-Rigid Variant of Huntington Disease,Chorea, Chronic Progressive Hereditary (Huntington),Chronic Progressive Hereditary Chorea (Huntington),Huntington Chronic Progressive Hereditary Chorea,Huntington Disease, Akinetic-Rigid Variant,Huntington Disease, Juvenile,Huntington Disease, Juvenile-Onset,Huntington Disease, Late Onset,Huntington's Chorea,Huntington's Disease,Juvenile-Onset Huntington Disease,Late-Onset Huntington Disease,Progressive Chorea, Chronic Hereditary (Huntington),Progressive Chorea, Hereditary, Chronic (Huntington),Akinetic Rigid Variant of Huntington Disease,Chorea, Huntington,Chorea, Huntington's,Huntington Disease, Akinetic Rigid Variant,Huntington Disease, Juvenile Onset,Huntington Disease, Late-Onset,Juvenile Onset Huntington Disease,Late Onset Huntington Disease
D012441 Saccharomyces cerevisiae A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement. Baker's Yeast,Brewer's Yeast,Candida robusta,S. cerevisiae,Saccharomyces capensis,Saccharomyces italicus,Saccharomyces oviformis,Saccharomyces uvarum var. melibiosus,Yeast, Baker's,Yeast, Brewer's,Baker Yeast,S cerevisiae,Baker's Yeasts,Yeast, Baker
D023081 CCAAT-Binding Factor A heterotrimeric DNA-binding protein that binds to CCAAT motifs in the promoters of eukaryotic genes. It is composed of three subunits: A, B and C. CCAAT-Binding Factor, A-Subunit,CCAAT-Binding Factor, B-Subunit,CCAAT-Binding Factor, C-Subunit,CBF Protein, CCAAT-Binding,CBF-A Protein, CCAAT-Binding,CBF-B Protein, CCAAT-Binding,CBF-C Protein, CCAAT-Binding,CCAAT-Binding Protein, CP1,CCAAT-Binding Transcription Factor,CCAAT-Binding-Factor,NF-Y Protein,CBF A Protein, CCAAT Binding,CBF B Protein, CCAAT Binding,CBF C Protein, CCAAT Binding,CBF Protein, CCAAT Binding,CCAAT Binding Factor,CCAAT Binding Factor, A Subunit,CCAAT Binding Factor, B Subunit,CCAAT Binding Factor, C Subunit,CCAAT Binding Protein, CP1,CCAAT Binding Transcription Factor,CCAAT-Binding CBF Protein,CCAAT-Binding CBF-A Protein,CCAAT-Binding CBF-B Protein,CCAAT-Binding CBF-C Protein,CP1 CCAAT-Binding Protein,Factor, A-Subunit CCAAT-Binding,Factor, B-Subunit CCAAT-Binding,Factor, C-Subunit CCAAT-Binding,NF Y Protein,Protein, CCAAT-Binding CBF-A,Protein, CCAAT-Binding CBF-B,Protein, NF-Y,Transcription Factor, CCAAT-Binding
D024101 Mitochondrial Proteins Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA. Proteins, Mitochondrial,Mitochondrial Protein,Protein, Mitochondrial
D029701 Saccharomyces cerevisiae Proteins Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes. Baker's Yeast Proteins,S cerevisiae Proteins

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