Heterochromatin protein 1 regulates longevity and the mitochondrial unfolded protein response
| Autor: | Cruz, Patricia de la, Askjaer, Peter, Artal-Sanz, Marta |
|---|---|
| Rok vydání: | 2021 |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Resumen del trabajo presentado en European Worm Meeting, celebrado en Vienna (Austria) del 27 al 30 de julio de 2022. Prohibitins (PHB-1 and PHB-2) form a large macromolecular structure at the mitochondrial inner membrane. PHB deficiency shortens the lifespan of wild type animals, but dramatically extends that of metabolically compromised animals, such as insulin/IGF-1 receptor (daf-2) mutants. This phenotype is accompanied by a differential induction of the mitochondrial Unfolded Protein Response (UPRmt), a stress-protective mechanism that is attenuated in daf-2 mutants. Through a genome wide RNAi screen, we identified Heterochromatin Protein 1 (HP1) as a new regulator of the UPRmt. HP1 proteins (HPL-1 and HPL-2 in C. elegans) bind histone H3 methylated on lysine 9 to maintain chromatin in a repressed state during development. Here we characterise the role of HPL-1 in mitochondrial functionality, in the response to mitochondrial stress and in mediating the opposing longevity phenotype caused by PHB depletion. Under normal conditions, hpl-1 null mutants live longer than wild type worms and show a mild induction of the UPRmt, which depends on canonical UPRmt transcription factors. We observed moderated mitochondrial fragmentation and reduced respiration in hpl-1 mutants, which together with a marked sensitivity to mitochondrial translation inhibition suggests a mitochondrial dysfunction. Remarkably, under mitochondrial stress by PHB depletion, hpl-1 null mutants showed an increased lifespan compared to wild type animals and a reduced UPRmt. The strong mitochondrial fragmentation caused by PHB depletion was not further affected by lack of HPL-1. However, the reduced respiration of PHB depleted animals was fully recovered in hpl-1 null mutants. Interestingly, HPL-1 was required for the increased lifespan and the attenuated UPRmt of daf-2 PHB-depleted worms. Under mitochondrial stress by phb-1 RNAi HPL-1 protein levels increase in hypodermal tissue, supporting the relevance of HPL-1 in mounting the stress response. Additionally, in the absence of stress HPL-1 levels increase as animals age, suggesting a role in longevity regulation. In order to study genes targeted by HPL-1, we examined its binding profile in hypodermal tissue by DamID under non-stress and mitochondrial stress conditions. HPL-1 was more regularly distributed along the genome than its HPL-2 homolog, which preferentially associates to chromosome arms. In addition, HPL-1 associated to coding and upstream regions with and without stress. Nevertheless, striking differences were found in a chromosome level, reflexed in less than 10% of bound genes shared in both conditions. Preliminary data uncovered a significant group of genes that are commonly regulated by different key stress transcription factors and HPL-1 under PHB depletion that could account for some phenotypes previously described. Lastly, under insulin signaling deficiency, there was a dramatic reduction in the regions bound by HPL-1, which was exacerbated upon mitochondrial stress in hypodermal tissue. |
| Databáze: | OpenAIRE |
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