Heterochromatin protein 1 and prohibitins regulate longevity and the Mitochondrial Unfolded Protein Response

Abstract

Prohibitins are conserved proteins of the inner mitochondrial membrane composed by PHB-1 and PHB-2 subunits. Whereas PHB deficiency shortens lifespan in wild type animals it dramatically increments lifespan in long-lived daf-2 animals. This phenotype is accompanied by a differential induction of the mitochondrial Unfolded Protein Response (UPRmt), which is attenuated in daf-2 mutants. Through a genome wide RNAi-based screening to determine mechanisms implicated in UPRmt induction upon PHB depletion in wild type and daf-2 animals, we identified Heterochromatin Protein 1 (HP1) as a new regulator of the UPRmt. HP1 proteins bind histone H3 methylated on lysine 9 to maintain chromatin in a repressed state during development. We observed an induction of the UPRmt in hpl-1 and hpl-2 single mutants as well as the double. Moreover, HP1 mutants exhibit decreased basal and maximal respiration confirming a mitochondrial dysfunction. Additionally, upon phb-1 RNAi, both HP1 proteins become more abundant in hypodermal tissue and HPL-2 in the germ line. Evaluation of the role on ageing of HP1 deletion mutants in wild type and daf-2 backgrounds under phb-1 RNAi uncovered that hpl-1 mutants exhibit an extended lifespan independent of phb-1 depletion. This could be related to the attenuated UPRmt response observed under PHB deficiency. Interestingly, hpl-1 is required for the enhanced longevity of PHB-depleted daf-2 mutants. Moreover, we found an increment of HPL-1 expression during aging, remaining steady in the case of HPL-2.