HSF-1 promotes longevity through ubiquilin-1 dependent mitochondrial network remodelling

Abstract

Abstract Increased activity of the heat shock factor, HSF-1, suppresses proteotoxicity and enhances longevity. However, the precise mechanisms by which HSF-1 promotes lifespan are unclear. Using an RNAi screen, we have identified ubiquilin-1 (ubql-1) as an essential mediator of lifespan extension in worms overexpressing hsf-1. We find that hsf-1 overexpression leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondria undergo extensive remodelling, leading to metabolic rewiring and increased lifespan. Together, our data are the first to establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to the down-tuning of organellar protein degradation pathways.