The regulation of redox homeostasis is an important field of study in cancer research. Actually, redox alterations is a mechanism that favours the clonal expansion of neoplastic cells. Thus, the multi-step pathway of neoplastic progression often includes mutations of the genes encoding the molecular machinery responsible of redox homeostasis. In this project we will try to identify a “mitochondrial functional module” operating during redox stress. The possibility that mitochondria could act as targets of redox alterations during tumoral cell transformation is an intriguing hypothesis supported by some considerations: mitochondria are the major source and the most proximal targets of reactive oxygen species and they regulate stress response and apoptosis, moreover agents perturbing mitochondrial Ca2+ homeostasis change the susceptibility of the cells to apoptosis. However, the mechanism by which mitochondria participate in the redox-dependent cellular neoplastic transformation is still unclear. The elucidation of these signalling pathways is the focus of this grant application. The work will focus on the identification of a “mitochondrial functional module” acting during redox stress. Much of a cell’s activity is in fact organized as a module composed by interacting molecules. In particular we will try to identify the molecules involved in mitochondrial Ca2+ homeostasis during redox changes (such as oxidant, reducing or antioxidants treatments) and the relevance of this regulation for the modulation of organelle function and cell fate. To this end we will pursue the preliminary results already obtained on the effects of redox stress on mitochondrial Ca2+ homeostasis, by investigating on the one hand their consequences on global cellular Ca2+ homeostasis, on the other the role of these changes on the sensitivity to apoptosis induced by different stimuli. We will then investigate the intracellular effectors of the redox mediated signals focusing on proteins interacting with the mitochondria. We will also investigate, by a variety of experimental approaches, the molecular mechanisms underlying the participation of these organelles during redox stress in different tumors. Finally, when a mitochondrial functional module will be identified, the expression profile of the proteins involved will be evaluated in normal and neoplastic cells. In these studies, we will employ a variety of experimental approaches that allow to image intracellular organelle structure, Ca2+ signals and effector proteins in living cells, including novel techniques (e.g. use of specifically targeted recombinant probes). Thus, in this grant proposal, we will combine the experimental approaches, the scientific know-how of the PI and the fundamental support from different external collaborators that ensure unique experience and expertise in all the fields, essentials for a new and young research unit. In conclusion, we believe that the identification of the “mitochondrial functional module” acting during redox-dependent neoplastic cellular transformation, with the elucidation of the intracellular targets and the molecules involved, can potentially reveal new pharmacological targets and allow in vitro test of the efficacy of pharmaceutical treatments to better identify the appropriate in vivo therapy.

Mitochondria as target of redox-mediated cellular transformation and its regulation by effector proteins

PINTON, Paolo
2008

Abstract

The regulation of redox homeostasis is an important field of study in cancer research. Actually, redox alterations is a mechanism that favours the clonal expansion of neoplastic cells. Thus, the multi-step pathway of neoplastic progression often includes mutations of the genes encoding the molecular machinery responsible of redox homeostasis. In this project we will try to identify a “mitochondrial functional module” operating during redox stress. The possibility that mitochondria could act as targets of redox alterations during tumoral cell transformation is an intriguing hypothesis supported by some considerations: mitochondria are the major source and the most proximal targets of reactive oxygen species and they regulate stress response and apoptosis, moreover agents perturbing mitochondrial Ca2+ homeostasis change the susceptibility of the cells to apoptosis. However, the mechanism by which mitochondria participate in the redox-dependent cellular neoplastic transformation is still unclear. The elucidation of these signalling pathways is the focus of this grant application. The work will focus on the identification of a “mitochondrial functional module” acting during redox stress. Much of a cell’s activity is in fact organized as a module composed by interacting molecules. In particular we will try to identify the molecules involved in mitochondrial Ca2+ homeostasis during redox changes (such as oxidant, reducing or antioxidants treatments) and the relevance of this regulation for the modulation of organelle function and cell fate. To this end we will pursue the preliminary results already obtained on the effects of redox stress on mitochondrial Ca2+ homeostasis, by investigating on the one hand their consequences on global cellular Ca2+ homeostasis, on the other the role of these changes on the sensitivity to apoptosis induced by different stimuli. We will then investigate the intracellular effectors of the redox mediated signals focusing on proteins interacting with the mitochondria. We will also investigate, by a variety of experimental approaches, the molecular mechanisms underlying the participation of these organelles during redox stress in different tumors. Finally, when a mitochondrial functional module will be identified, the expression profile of the proteins involved will be evaluated in normal and neoplastic cells. In these studies, we will employ a variety of experimental approaches that allow to image intracellular organelle structure, Ca2+ signals and effector proteins in living cells, including novel techniques (e.g. use of specifically targeted recombinant probes). Thus, in this grant proposal, we will combine the experimental approaches, the scientific know-how of the PI and the fundamental support from different external collaborators that ensure unique experience and expertise in all the fields, essentials for a new and young research unit. In conclusion, we believe that the identification of the “mitochondrial functional module” acting during redox-dependent neoplastic cellular transformation, with the elucidation of the intracellular targets and the molecules involved, can potentially reveal new pharmacological targets and allow in vitro test of the efficacy of pharmaceutical treatments to better identify the appropriate in vivo therapy.
2008
Pinton, Paolo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1399597
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