Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, Division of Biosciences, University College London, London, UK.
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.
Nat Commun. 2024 Nov 12;15(1):9797. doi: 10.1038/s41467-024-54136-x.
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.
热休克因子 HSF-1 的活性增加可抑制蛋白毒性并延长寿命。然而，HSF-1 促进寿命的确切机制尚不清楚。通过 RNAi 筛选，我们确定泛素结合酶 1（ubiquilin-1，ubql-1）是 hsf-1 过表达延长蠕虫寿命的必需介质。我们发现 hsf-1 过表达导致 CDC-48-UFD-1-NPL-4 复合物的所有成分的转录下调，该复合物是内质网和线粒体相关蛋白降解的核心，而这可以通过 UBQL-1 依赖性 NPL-4.1 的周转来补充。结果，线粒体网络动力学发生改变，导致寿命延长。总之，我们的数据表明，HSF-1 通过线粒体网络适应来延长寿命，这种适应是对与细胞器蛋白降解途径相关的成分下调的反应。
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