title: Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging.
abstract: Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through whichHAP4overexpression exerts this protection remains unclear. Furthermore, it remains unexplored whetherHAP4overexpression and increased respiratory function during growth can also protect against polyQ-induced toxicity during yeast chronological lifespan. Here, we show that in yeast, mitochondrial respiration and oxidative phosphorylation (OXPHOS) are essential for protection against the polyQ-induced growth defect byHAP4overexpression. In addition, we show that not only increasedHAP4levels, but also alternative interventions, including calorie restriction, that result in enhanced mitochondrial biogenesis confer protection against polyQ toxicity during stationary phase. The data obtained in yeast models guided experiments in a fly model of HD, where we show that enhancement of mitochondrial biogenesis can also protect against neurodegeneration and behavioral deficits. Our results suggest that therapeutic interventions aiming at the enhancement of mitochondrial respiration and OXPHOS could reduce polyQ toxicity and delay disease onset.
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Ruetenik
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ocampo
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ruan
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Human Genetics and Genomics Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Human Genetics and Genomics Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: R Grace
authors.initials: RG
authors.lastname: Zhai
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Barrientos
keywords: Drosophila model; Saccharomyces cerevisiae; caloric restriction; mitochondrial OXPHOS; mitochondrial biogenesis; mitochondrial respiration; polyglutamine toxicity; yeast chronological life span