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

Annmary Paul Erinjeri, Xunyan Wang, Rhianna Williams, Riccardo Zenezini Chiozzi, Konstantinos Thalassinos and Johnathan Labbadia ()
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Annmary Paul Erinjeri: University College London
Xunyan Wang: University College London
Rhianna Williams: University College London
Riccardo Zenezini Chiozzi: University College London
Konstantinos Thalassinos: University College London
Johnathan Labbadia: University College London

Nature Communications, 2024, vol. 15, issue 1, 1-15

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 identify 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, mitochondrial network dynamics are altered, leading to increased lifespan. Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.

Date: 2024
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DOI: 10.1038/s41467-024-54136-x

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