Heterochromatin Protein 1 controls gene expression and longevity upon prohibitin depletion

Abstract

Trabajo presentado en el VIII Spanish Worm Meeting, celebrado en Logroño (España) del 21 al 22 de octubre de 2022.Prohibitins (PHB) form a multimeric structure at the mitochondrial inner membrane. PHB deficiency shortens the lifespan of wild type Caenorhabditis elegans nematodes, but dramatically extends that of insulin signalling receptor (daf-2) mutants. This phenotype is accompanied by a differential induction of the mitochondrial Unfolded Protein Response (UPRmt) that is attenuated in daf-2 mutants. In a genome wide RNAi screen, we identified Heterochromatin Protein Like 1 (HPL-1) as a new regulator of the UPRmt. 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 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. Moreover, 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. Upon PHB depletion, 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 in wild type and daf-2 mutants. HPL-1 associates to coding and upstream regions with and without stress. We uncovered ~40% and 70% of HPL-1-unique bound genes upon mitochondrial stress in wild type and insulin signalling mutants, respectively. Among them, a significant group of genes are commonly regulated by HPL-1 and key stress transcription factors and epigenetic regulators under the different conditions. Our data shows for the first time a role for HP1 proteins in controlling gene expression in response to mitochondrial dysfunction to modulate lifespan