TRANSMIT - Translational significance of mitochondrial mutations in tumors

Mitochondria play a pivotal role in energy metabolism, apoptosis and calcium regulation. They are endowed with their own genome, encoding subunits of respiratory chain complexes. The crosstalk between the nuclear and the mitochondrial genome (mtDNA) is essential for cell functions. MtDNA mutations have been associated to cancer although their functional relationship with tumor development has been seldom analyzed. We recently focused on the role of mitochondrial mutations in tumors characterized by abnormal mitochondrial proliferation, namely thyroid and renal oncocytoma. Oncocytic tumors derive mainly from epithelial thyroid and kidney, but occur also in parathyroid, salivary, pituitary glands and breast. Recently, we identified a frameshift change in the ND1 gene, causing a dramatic decrease in complex I activity in XTC.UC1 cells, a model of thyroid oncocytic tumor. An extensive screening on over 100 tumors allowed us to associate truncating mutations in complex I with the oncocytic phenotype. Most mutations were both disruptive and homoplasmic, possibly preventing a correct complex assembly. Moreover, we have reported a peculiar case of shift to homoplasmy occurring exclusively in tumor cells of an inherited disruptive mtDNA mutation. All data collected so far indicate that the homoplasmic shift of non-neutral mutations may be associated with mitochondrial biogenesis regulation. Pathogenic mtDNA mutations should force cancer cells to rely on glycolysis for energy production, explaining the so-called Warburg effect (glycolytic shift), which may also be sustained by a pseudohypoxic condition similar to that occurring in succinate dehydrogenase and fumarate hydratase mutated tumors. The main common feature of these tumors is a chronic pseudohypoxic status, due to aberrant hypoxia-inducible factor (HIF1α) stabilization. HIF1 is a critical player in mediating the metabolic adaptation needed to progress from a benign to a malignant state. Nonetheless, oxygen radicals-dependent HIF1α stabilization may only be triggered if a functional respiratory chain is present. In this context, the behavior of mtDNA mutations may be dual, according to whether the mutation impairs complex assembly and function or merely its function. It is therefore of paramount importance to understand whether the shift to homoplasmy occurring in tumor cells is an actively controlled mechanism, since this may determine the metabolic and adaptive fate of tumor cells within the tumorigenic process. The dissection of the cellular pathways involved in such shift may in fact explain the apparent paradox that cells bearing a substantial energetic defect may have a selective growth advantage. Hence, the only mechanism that could lead to the homoplasmic shift of mtDNA mutations is the induction of mitochondrial biogenesis through the replication of the mitochondrial genome. One of the major aims of this project is to understand which stimuli are involved in regulating mitochondrial biogenesis to induce such shift. We propose here three alternatives: a retrograde signalling from the mitochondria to the nucleus, alterations of mitochondrial fission and a receptor-mediated signalling pathway, triggered by an oncogenic stimulus. In conclusion the present project will attempt to shed light on the debate over the role of mtDNA mutations in cancer and the mechanisms underlying the metabolic adaptation of transformed cells