|Cell Biology and Immunology|
Biogenesis and function of mitochondria and its role in pathology
José M. Cuezva
The Role of Mitochondria in Human Pathology: We are interested in the characterization of the cellular and molecular mechanisms that regulate the activity of mitochondria in cells of mammals. Our studies are focused on the H+-ATP synthase complex, the enzyme system that is bottle-neck for the generation of biological energy by oxidative phosphorylation (OXPHOS) and that is also required for the execution of cell death. Because mitochondrial dysfunction is at the heart of different human pathologies (ageing, cancer, diabetes, neurodegeneration and rare diseases) we pay particular emphasis to the study of the mechanisms that promote an aberrant mitochondrial phenotype. More specifically, of the mechanisms associated with primary defects affecting the expression and/or activity of the H+-ATP synthase. Recently, we have demonstrated: (i) that regulation of the expression of the catalytic subunit (β-F1-ATPase) of the human H+-ATP synthase is exerted at the level of translation both during development and in oncogenesis (Fig. 1A); (ii) characterized the mechanisms and signaling pathways that promote metabolic rewiring in cancer cells (Fig. 1B) and (iii) demonstrated that many prevalent human carcinomas over-express the ATPase Inhibitory Factor 1 (IF1) (Fig. 2A). In contrasts to previous suggestions, we have demonstrated that IF1 acts in vivo as an inhibitor of the H+-ATP synthase (Fig. 2B). Mechanistically, the over-expression of IF1 triggers the inhibition of OXPHOS promoting metabolic rewiring of the cancer cell to an enhanced aerobic glycolysis (Fig. 2B). Moreover, by blocking the activity of the H+-ATP synthase, IF1 promotes a ROS signal that orchestrates the transcriptional activation of a cell-type specific adaptive response to favour an enhanced proliferation and cell death resistance (Fig. 2B). Moreover, we have developed conditional tissue-specific transgenic mice to inhibit the activity of the H+-ATP synthase by the regulated expression of IF1 to deepen in the molecular characterization of the biological functions of IF1.
1 - Formentini L, Pereira MP, Sánchez-Cenizo L, Santacatterina F, Lucas JJ, Navarro C, Martínez-Serrano A, Cuezva JM. (2014) In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning. EMBO J. 33(7):762-78.
2 - Sánchez-Aragó M, García-Bermúdez J, Martínez-Reyes I, Santacatterina F, Cuezva JM. (2013) Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep. 14(7):638-44.
3 - Sánchez-Aragó M, Formentini L, Martínez-Reyes I, García-Bermudez J, Santacatterina F, Sánchez-Cenizo L, Willers IM, Aldea M, Nájera L, Juarránz A, López EC, Clofent J, Navarro C, Espinosa E, Cuezva JM. (2013) Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Oncogenesis. 2:e46.
4 - Sánchez-Aragó M, Formentini L, Cuezva JM. (2013) Mitochondria-mediated energy adaption in cancer: the H(+)-ATP synthase-geared switch of metabolism in human tumors. Antioxid Redox Signal. 19(3):285-98.
5 - Formentini L, Sánchez-Aragó M, Sánchez-Cenizo L, Cuezva JM. (2012) The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell. 45(6):731-42.
- The research group is:
(i) Unit 713 of CIBERER, in the field of Mitochondrial Pathology of the CIBER de Enfermedades Raras, Instituto de Salud Carlos III;
(ii) "Translation of Energy Metabolism" group of the field of Cancer of the Instituto de Investigación Hospital 12 de Octubre (i+12) and
(iii) forms part and coordinates the MITOLAB Consortium of the Comunidad de Madrid.
- J.M. Cuezva, (2011) was President of the Evaluation Panel of "Molecular and Cellular Biology" of the National Evaluation Committee of Scientific Activity (CNEAI).
- The laboratory has recently launched the PROTEOmAb Service (2012) that is aimed at the identification and quantification of new molecular markers of disease and/or of the response to therapy based on "Reverse Phase Protein Microarray" technologies. The idea is to help the scientific/clinical community in the evaluation and translation of markers of energy metabolism.
Fulvio Santacatterina, María Sanchez-Arago and Jose M. Cuezva. “Un proceso y kit para el diagnóstico diferencial de una enfermedad que cursa con afectación muscular”. Application number: 201230771. Publication number: ES2432653. Country: Spain. Priority date: 23/05/2012. Applicants: Universidad Autónoma de Madrid-CIBERER
1.- Laura Sánchez Cenizo (2014) "Función oncogénica del inhibidor de la H+-ATP sintasa, IF1: desarrollo y caracterización de modelos transgénicos condicionales y tejido-específicos". Universidad Autónoma de Madrid. Director: José M. Cuezva.
2.- Inmaculada Martínez Reyes (2012) "Mecanismos y vías de señalización implicados en la reprogramación metabólica en cáncer de colon”. Universidad Autónoma de Madrid. Director: José M. Cuezva.
3.- Imke M. Willers (2011) "Molecular mechanisms controlling the translation of the mRNA encoding the human catalytic β-subunit of mitochondrial H+-ATP synthase in cancer and development”. Universidad Autónoma de Madrid. Directors: José M. Cuezva and Álvaro D. Ortega.