Mitochondrial defects are associated with aging and age-related pathology, but the molecular mechanisms regulating mitochondrial function during ageing are poorly understood. The most relevant genetic pathway regulating ageing is the insulin/IGF-1 signalling (IIS) pathway. The mitochondrial prohibitin (PHB) complex influences cellular metabolism and mitochondrial biogenesis, affecting ageing in opposite ways in wild-type animals and IIS-defective C. elegans mutants. The aim of the proposed research programme is to shed light on the intricate communication between mitochondria and cell-signalling networks in the regulation of ageing. Our specific objectives are: 1-Elucidate the cellular signalling pathways involved in the metabolic responses to mitochondrial dysfunction upon PHB depletion in wild type animals and IIS-defective mutants, using genome-wide RNAi screens, 2-Conduct a comprehensive metabolic profiling of wild type and IIS mutants in the presence and absence of prohibitins and 3-Identify genetic suppressors of prohibitins by performing forward genetic suppressor screens. As an ultimate goal, genes discovered in C. elegans will be tested in vertebrate assays for a conserved role in ageing. We will implement an interdisciplinary approach that combines the genetic power of C. elegans with state-of-the-art metabolomic approaches as well as automated sorting and optical imaging technologies to monitor fat content and mitochondrial biogenesis, in a genome-wide scale, in vivo. The fine-tuning of cellular metabolism, by integration of diverse signalling inputs is the molecular basis of longevity. This project represents a truly integrative and innovative approach to identify cellular signalling pathways involved in mediating lifespan-extending metabolism adjustments, and what these metabolic adjustments entail. These studies will provide fundamental insights to understand the ageing process and to combat ageing-related diseases.
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