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Projects. Life and Earth Sciences

The oncogenic function of IF1: the inhibitor of mitochondrial H+-ATP syntase

Lead Researcher:
José Manuel Cuezva Marcos

Research Centre:
Centro de Biología Molecular Severo Ochoa. CSIC-UAM.

Abstract: 

José Manuel Cuezva MarcosMitochondrial dysfunction is involved in the genesis and/or progression of many human pathologies. A key protein complex in the generation of energy in the mitochondria is H+-ATP syntase, which can synthesise or hydrolyse ATP depending on cellular conditions. H+-ATP syntase is involved in a molecular and functional way in the execution of cell death by mitochondrial means. In human carcinomas the expression of H+-ATP syntase is lower than it is in healthy tissues, this being a bioenergetic sign of disease progress, as well as tumoral response to therapy. Additionally, we have also described how Factor Inhibitor 1 of the ATPasa (IF1) is over expressed in cancer. We have proven that IF1 inhibits hydrolytic activity (ATPasa) as well as ATP synthesis. The inhibition of H+-ATP syntase mediated by IF1 promotes the metabolic reprogramming of the tumoral cells to active glucolysis, as well as a signal of oxygen-reactive types that activate proliferation, invasion and resistance against cell death programs. IF1 is therefore configured as a very important mitochondrial protein for the definition of the energy metabolism, tissue homeostasis and programmed death. The overall aim of this project is to enhance knowledge of the cellular biology of IF1 and its involvement in cancer, adding to knowledge about a new route for the prevention, diagnosis and therapies for colon cancer. Its specific aims are: (i) to identify the post-transcriptional mechanisms which regulate the expression and activity of IF1; (ii) in vivo characterisation of the role of IF1 in cancer progression and metastasis, and (iii) to identify the molecules which regulate the activity of IF1 and which may contribute to the development of a therapeutic design for colon cancer using IF1 as the target.


Researcher's web address:
http://www.cbm.uam.es/jmcuezva.



José Manuel Cuezva Marcos

Graduate in Biology from the University of the Basque Country (UPV), doctorate from the Universidad Autónoma de Madrid (UAM) (1978) for his work on the energy metabolism of the newborn under the direction of Professor José María Medina Jiménez (CBMSO). He spent his postdoctoral period in Case Western Reserve University, Cleveland, USA, studying metabolic alterations in babies born of diabetic mothers in the laboratory of Professor Mulchand Patel. He was named Assistant Permanent Professor of Biochemistry (1983) and Professor of Biochemistry and Molecular Biology (1998) of the Molecular Biology Department of the UAM, of which he is now director. Since returning to Spain he has combined his teaching activity with leadership of a research group which has the main purpose of studying mitochondrial biogenesis and function, as well as its repercussions in pathology. He became involved in the study of bioenergetic dysfunction of the mitochondria in cancer approximately fifteen years ago. In this context, he spent a sabbatical period in the Burham Institute, La Jolla, California (2001) in the laboratory of Dr. John C. Reed. He is a member of the Research centre Biomédica en Red de Enfermedades Raras and of the Instituto de Investigación Hospital 12 de Octubre de Madrid.


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