TRANSMIT - Significato funzionale delle mutazioni mitocondriali nel cancro

Mitochondria are cytosolic organelles whose multi-faceted roles are essential for cellular homeostasis. In fact mitochondria play a pivotal role in energy metabolism, apoptosis, calcium regulation and cell components biosynthesis. These organelles are endowed with their own genome, a multicopy circular chromosome, about 16560 bp long, encoding also key subunits of respiratory chain complexes. The crosstalk between the nuclear and the mitochondrial genome (mtDNA) is essential for mitochondrial and cell function. MtDNA mutations have been associated to cancer although their functional relationship with tumor development has been seldom analyzed. TOne of the major aims of this project is to understand how the mechanisms regulating mitochondrial biogenesis may act to induce the homoplasmic shift of mtDNA mutations, and what types of specific stimuli are involved. Such mechanisms, which would allow the mutations to propagate, are not known. We propose here three alternatives: a retrograde signalling from the mitochondria to the nucleus, due to hypoxia or mutations in mtDNA, alterations of mitochondrial network dynamics and a receptor-mediated signalling pathway, triggered by an oncogenic stimulus, such as the pleiotropic inflammatory mediator interleukin 6, whose role in cancer is still ambiguous. In conclusions, in order to shed light on the still hot debate over the role of mtDNA mutations in cancer and the mechanisms underlying the metabolic adaptation of transformed cells, we will undertake the following challenges: - to demonstrate whether mitochondrial mutations, particularly in complex I, have a causative or a modifier effect in tumor formation/progression in vitro and in vivo, by exploiting the unique cell models available at the Coordinator’s unit; - to unravel the role of mtDNA mutations and their different degrees of heteroplasmy on HIF1-driven metabolic adaptation of the tumor; - to investigate the tumorigenic potential of missense and disruptive mtDNA mutations, taking into account their degree of heteroplasmy and their impact on respiratory complexes function and assembly; - to dissect the molecular mechanisms underlying the positive selection (homoplasmic shift) of mtDNA mutations and controlling metabolic adaptation, by investigating mitochondrial biogenesis, its connections with HIF1-related pathways and the possible role of a pleiotropic inflammatory mediator.