Two conserved transcription factors and a histone deubiquitinase regulate the mitochondrial unfolded protein response and longevity interacting with insulin signalling.

Abstract

Abstract Ageing is characterized by physiological decline and increased risk of agerelated diseases. The mitochondrial prohibitin (PHB) complex, a ringlike structure in the inner mitochondrial membrane, is critical to mitochondrial function and proteostasis. Depletion of PHB has opposite effects on ageing, shortening lifespan in wildtype worms while extending the lifespan of different metabolically compromised animals, including that of insulin/IGF-1like signalling (IIS) receptor mutants daf-2(e1370). Lack of PHB strongly induces the mitochondrial unfolded protein response (UPRmt) to maintain mitochondrial proteostasis, while daf-2 mutants attenuate the UPRmt triggered by PHB depletion. In this study, we aimed at identifying new pathways involved in the regulation of the PHBmediated mitochondrial stress response, as well as mechanisms responsible for the opposite longevity outcomes of PHB depletion. Towards this aim, we carried out a genomewide double RNAi screen, depleting C. elegans genes having a human orthologue, in PHBdepleted otherwise wild-type animals and PHBdepleted IIS mutants. We uncovered both known and new PHB genetic interactors affecting the UPRmt in the different genetic backgrounds. We identified two new transcription factors ZNF-622 and TLF-1 as specific regulators of the mitochondrial stress response. We further established chromatin remodelling via the histone deubiquitination protein USP-48 as a strong differential modulator of the mitochondrial stress response and ageing in wild-type and IIS mutants. Furthermore, we suggest USP-48 as a regulator of gene expression upon mitochondrial stress and defective IIS signalling as its nuclear expression is elevated in such conditions. Finally, we observe that the UPRmt induction by lack of USP-48 is largely independent of ATFS-1 and fully independent of DVE-1, the canonical UPRmt transcription factors. Interestingly, lack of USP-48 increases nuclear DVE-1 levels, while DVE-1 depletion further increases the UPRmt in usp-48 mutants. Overall, this study identifies new players specifically involved in the regulation of the mitochondrial stress response and longevity and sheds light on the processes contributing to the differential effect in ageing of PHB depletion in wild-type and metabolically compromised animals.