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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 338-351 |
| Number of pages | 14 |
| Journal | Microbial Cell |
| Volume | 3 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2016 |
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Keywords
- Caloric restriction
- Drosophila model
- Mitochondrial biogenesis
- Mitochondrial OXPHOS
- Mitochondrial respiration
- Polyglutamine toxicity
- Saccharomyces cerevisiae
- Yeast chronological life span
ASJC Scopus subject areas
- Immunology and Microbiology (miscellaneous)
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cite this
Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging. / Ruetenik, Andrea L.; Ocampo, Alejandro; Ruan, Kai; Zhu, Yi; Li, Chong; Zhai, Rong G; Barrientos, Antonio.
In: Microbial Cell, Vol. 3, No. 8, 01.08.2016, p. 338-351.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging
AU - Ruetenik, Andrea L.
AU - Ocampo, Alejandro
AU - Ruan, Kai
AU - Zhu, Yi
AU - Li, Chong
AU - Zhai, Rong G
AU - Barrientos, Antonio
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Caloric restriction
KW - Drosophila model
KW - Mitochondrial biogenesis
KW - Mitochondrial OXPHOS
KW - Mitochondrial respiration
KW - Polyglutamine toxicity
KW - Saccharomyces cerevisiae
KW - Yeast chronological life span
UR - http://www.scopus.com/inward/record.url?scp=85043338646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85043338646&partnerID=8YFLogxK
U2 - 10.15698/mic2016.08.518
DO - 10.15698/mic2016.08.518
M3 - Article
AN - SCOPUS:85043338646
VL - 3
SP - 338
EP - 351
JO - Microbial Cell
JF - Microbial Cell
SN - 2311-2638
IS - 8
ER -