A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse

Dev Cell. 2020 Sep 28;54(6):758-772.e5. doi: 10.1016/j.devcel.2020.06.038. Epub 2020 Jul 30.

Abstract

The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. In Caenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.

Keywords: HSF1; PP2A; aging; mitochondria; molecular chaperones; protein aggregation; proteostasis; stress responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / metabolism*
  • Heat-Shock Response / physiology
  • Mitochondria / metabolism*
  • Molecular Chaperones / metabolism
  • Proteome / metabolism
  • Proteostasis / physiology*
  • Stress, Physiological / physiology
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Molecular Chaperones
  • Proteome
  • Transcription Factors
  • heat shock factor-1, C elegans