Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging
Authors:Andrea L. Ruetenik1,2,3, Alejandro Ocampo1,2,3,¶, Kai Ruan4,5,#, Yi Zhu4,5, Chong Li4,6, R. Grace Zhai1,4,5,6 and Antoni Barrientos1,2,3,5
doi: 10.15698/mic2016.08.518
Volume 3, pp. 338 to 351, published 26/07/2016.
1 Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
2 Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
3 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
4 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
5 Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
6 Human Genetics and Genomics Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
¶ Current Address: Gene Expression Laboratory. The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
# Current Address: Department of Neurology, School of Medicine, Johns Hopkins University, Maryland 21205, USA.
Keywords:
Saccharomyces cerevisiae, mitochondrial respiration, mitochondrial OXPHOS, mitochondrial biogenesis, polyglutamine toxicity, yeast chronological life span, Drosophila model, caloric restriction.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Andrea L. Ruetenik, Alejandro Ocampo, Kai Ruan, Yi Zhu, Chong Li, R. Grace Zhai and Antoni Barrientos (2016). Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging. Microbial Cell 3(8): 338-351. doi: 10.15698/mic2016.08.518
© 2016 Ruetenik et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
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 which HAP4 overexpression exerts this protection remains unclear. Furthermore, it remains unexplored whether HAP4 overexpression 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 by HAP4 overexpression. In addition, we show that not only increased HAP4 levels, 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.