White Rose BBSRC DTP CASE with Nanna Therapeutics - Exploring a novel biological role of the master energy homeostasis regulator PGC1α as a potential modifier of mitochondrial function and senescence

Alteration of the energy metabolism and mitochondrial dysfunction are known features of ageing and manipulating mitochondrial function through caloric restriction prolongs survival. The master energy regulator PGC1α plays a pivotal role in controlling the antioxidant response and the energy metabolism homeostasis through transcriptional co-activation of genes involved in mitochondrial biogenesis and function. It plays key regulatory metabolic functions in muscles, liver, adipocytes and neurons. PGC1α-dependent regulatory pathways are down-regulated in age and age-related diseases which include muscle wasting and some metabolic and neurodegenerative disorders. Consistent with this, increased and decreased expression levels of PGC1α have respectively been associated with cell survival in stress conditions and premature ageing in flies. The transcriptional co-activating function of PGC1α has been thoroughly studied with over 4,000 published articles in the past 20 years however the putative RNA recognition motif of PGC1α has remained poorly investigated. We recently discovered that PGC1α plays a new role in the processing of PGC1α-activated mRNAs encoding some mitochondrial-related proteins in human embryonic kidney cells. In this fully-funded 4-year White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology, the newly-uncovered biological function of PGC-1α will be investigated in physiologically-relevant senescent and neuronal cell models, applying cutting-edge techniques and compound tools in collaboration with a leading mitochondrial startup company, Nanna Therapeutics. More specifically, the successful PhD candidate will evaluate the physiological relevance of the transcriptional co-activation and RNA processing functions of PGC-1α, their potential alterations and the effects of manipulating the expression of PGC1α as well as of boosting mitochondrial function in bone marrow derived human mesenchymal stem cell models of senescence and in young and old patient-derived neurons differentiated from induced neural progenitor cells reprogrammed from the fibroblasts of young and old healthy individuals.