The Role of Mitochondria in Human Pathology
Mitochondria play key roles in cellular metabolism, bioenergetics, the execution of cell death and intracellular signaling. Consistent with its prime physiological roles mitochondrial dysfunction is involved in the genesis and progression of ageing and of a plethora of human pathologies including cancer, metabolic syndrome, neurodegeneration and rare disorders. The mitochondrial ATP synthase is a key transducer in energy conservation by oxidative phosphorylation (OXPHOS), in the execution of cell death and in intracellular signaling by calcium and reactive oxygen species (ROS). Previously, we documented the mechanisms and role-played by the ATP synthase in metabolic reprogramming during liver development and in human carcinomas. More recently, we demonstrated that the inhibitor of the ATP synthase, named ATPase Inhibitory Factor 1 (IF1), is highly overexpressed in carcinomas playing a pivotal role in metabolic reprogramming of cancer and stem cells. We showed that binding of IF1 to the ATP synthase inhibits the enzyme under normal physiological conditions and this binding is prevented by phosphorylation of IF1-S39 through the activity of a cAMP-dependent protein kinase A like activity. Inhibition of the ATP synthase is required for adaptation to hypoxia, cell cycle progression and in cancer. Contrariwise, dephosphorylation of IF1 is required to increase the mitochondrial output of ATP in response to an increase in energy demand. Moreover, the IF1-mediated inhibition of the ATP synthase triggers a ROS signal that promotes the activation of nuclear programs of proliferation and resistance to cell death. Hence, IF1 is a most relevant mitochondrial protein that participates in defining the cellular phenotype.
A main objective of our group is to deepen into the cellular biology and role of the ATP synthase/IF1 axis in cancer and other metabolic disorders, neuronal and immune functions and in ageing. To cover these aims, we have developed transgenic mice (Tg-IF1) that conditionally overexpress human IF1 in neurons, liver, colon, heart and skeletal muscle, and generated the ATP5IF1 lox/lox mouse which has been successfully used to knock-out IF1 (IF1-KO) in neurons, enterocytes and immune cells. With these models, we have demonstrated in vivo the role of the ATP synthase/IF1 in metabolic reprogramming and in signaling adaptive cellular and tissue responses in normal and pathophysiological situations (Fig. 1). Moreover, we have developed (i) the PROTEOmAb Platform for the identification of metabolic proteins as biomarkers of disease and (ii) identified FDA-approved small molecules that regulate OXPHOS for targeting mitochondria and effective bedside translation of the drugs to patients affected by mitochondrial dysfunction.