Biogenesis and function of mitochondria and its role in pathology
Mitochondria play key roles in metabolism, the execution of cell death and intracellular signaling. Consistent with the prime physiological roles of mitochondria its dysfunction is involved in the genesis and progression of ageing and of a plethora of pathologies including cancer and neurodegeneration.
The mitochondrial ATP synthase is a key transducer in energy conservation and in signaling, in shaping the structure of cristae and in the execution of death. Previously, we have documented that the expression of the ATP synthase is partially repressed in human carcinomas providing a “bioenergetic signature” of disease progression. More recently, we have described that its inhibitor, the ATPase Inhibitory Factor 1 (IF1), is highly overexpressed in most prevalent carcinomas and demonstrated that it plays a prominent role in metabolic reprogramming of tumor cells and during differentiation of stem cells.
Moreover, the IF1-mediated inhibition of the ATP synthase triggers a ROS signal that promotes the activation of nuclear programs aimed at cell survival. We have developed transgenic mice that conditionally express IF1 in neurons, hepatocytes, intestinal epithelium or heart and demonstrated in vivo the role of IF1 in metabolic reprograming and nuclear signaling “mitohormetic” responses, including the mechanisms by which IF1 overexpression promotes a pro-oncogenic phenotype in liver (Fig. 1).
Furthermore, we have succeeded in the generation of the ATPIF1 lox/lox mice for the development of IF1-KO mice in different tissues and demonstrated that the binding of IF1 to the ATP synthase, which promotes the inhibition of the enzyme in hypoxia, cell cycle and in cancer, is regulated by the activity of a mitochondrial cAMP-dependent protein kinase (Fig. 2). Hence, IF1 is a most relevant mitochondrial protein that defines the cellular phenotype.
Our main objective is to deepen into the knowledge of the cellular biology of IF1 and of its implication in cancer, neuronal function and in ageing.
