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

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. [Display omitted] •Mitochondrial stress promotes HSF-1 dephosphorylation through the PP2A complex•Hypo-phosphorylated HSF-1 drives a stress response that is enriched for small HSPs•Mitochondria protect against cytosolic protein aggregation through small HSPs•Overexpressing the PP2A catalytic subunit suppresses proteostasis collapse Using the worm Caenorhabditis elegans as a model system, Williams et al. demonstrate that in response to developmental electron transport chain impairment, HSF-1 activity is re-modeled in adulthood by the PP2A complex. This results in the preferential up-regulation of small heat shock proteins, thereby protecting the cytosol against proteostasis collapse.