Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging

Andrea L. Ruetenik, Alejandro Ocampo, Kai Ruan, Yi Zhu, Chong Li, Rong G Zhai, Antonio Barrientos

Research output: Contribution to journalArticle

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)338-351
Number of pages14
JournalMicrobial Cell
Volume3
Issue number8
DOIs
StatePublished - 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)

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