Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

Cell Rep. 2017 Nov 7;21(6):1481-1494. doi: 10.1016/j.celrep.2017.10.038.

Abstract

In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes. This resulted in a robust restoration of cytoplasmic proteostasis and increased vitality later in life, without detrimental effects on fecundity. We propose that low levels of mitochondrial stress regulate cytoplasmic proteostasis and healthspan during aging by coordinating the long-term activity of HSF-1 with conditions preclusive to optimal fitness.

Keywords: HSF-1; aging; heat shock response; mitochondria; proteostasis; stress resistance.

MeSH terms

  • Aging*
  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cytoplasm / metabolism
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electron Transport Chain Complex Proteins / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Heat-Shock Response / genetics*
  • Longevity
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Protein Binding
  • Proteostasis / physiology
  • RNA Interference
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological
  • Temperature
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Xenobiotics / pharmacology

Substances

  • Caenorhabditis elegans Proteins
  • Electron Transport Chain Complex Proteins
  • Heat-Shock Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Transcription Factors
  • Xenobiotics
  • heat shock factor-1, C elegans
  • RNA Polymerase II