Basic Research Departments - CNIC

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S C I E N T I F I 2C R E P O R T 2 0 1 0 Basic Research Departments Functional genetics of the oxidative phosphorylation system RESEARCH INTEREST Head of Laboratory: José Antonio Enríquez Research Scientists: Acisclo Pérez Martos Patricio Fernández Silva Erika Fernández -Vizarra Nuria Garrido Pérez Pilar Bayona Bafaluy Postdoctoral Researchers: Carmen Colás Esteban Ester Perales Clemente Patricia Meade Huerta Raquel Moreno Loshuertos Predoctoral Researchers: Ricardo Marco Lázaro Adela María Guaras Rubio Ana Latorre Pellicer Esther Lapuente Brun Elena de Tomás Mateo Support Scientists: Mª Concepción Jiménez Gómez Nieves Movilla Meno Marta Roche Molina Visiting Scientists: Eduardo Balsa Martinez Sara Cogliati Disorders of the mitochondrial oxidative phosphorylation (OXPHOS) system are among the most common inherited metabolic disorders, affecting an estimated 1 in every 5000 live births. The mitochondrial OXPHOS system comprises the four respiratory chain complexes (complexes I, II, III and IV) and ATP synthase (complex V), and is the major source of ATP in eukaryotic cells. The mtDNA mutations associated with the clinical phenotypes of these diseases fall into three main categories: 1) Point mutations affecting either protein synthesis genes (rRNA and tRNA) or mtDNA-encoded structural OXPHOS subunits;2) Rearrangements, which can be single or multiple deletions or partial duplications; 3) Depletions, in which the amount of mtDNA is significantly reduced. Although these mtDNA defects are seldom associated solely with cardiomyopathy, they have serious effects on cardiac tissue because OXPHOS-derived ATP is essential for the heart’s contractile activity. After encephaloneuromuscular syndromes, cardiomyopathy, predominantly cardiac hypertrophy, is the most common pathology associated with mtDNA point mutations. 27 Regenerative Cardiology We use a range of approaches to investigate the role of the OXPHOS system in health and disease. One reason for the current limited knowledge in this area is that established models of electron transport chain organization are flawed. To address this, we are implementing high-throughput strategies to catalogue the set of the genes whose products participate in the biogenesis and regulation of the OXPHOS system (which we call the OXPHOME). We are also determining the factors that regulate the structural organization of the electron transport chain and the role that this superstructural organization plays in the production of reactive oxygen species (ROS). This area is linked to our interest in the role of ROS as mitochondrial second messengers and to our aim to deconstruct, in cellular models, the mammalian OXPHOS system into its functional components (electron transport, proton pumping and ATP synthesis).
S C I E N T I F I C R E P O R T 2 0 1 0 2 Regenerative Cardiology MAJOR GRANTS - Ministerio de Ciencia e Innovación (SAF2009-08007) - Ministerio de Ciencia e Innovación CONSOLIDER Project (CSD2007-00020) SELECTED PUBLICATIONS Schematic representation of the OXPHOS system embedded in the mitochondrial inner membrane (top) and the genes encoded by human mtDNA (bottom). ND genes, the seven mtDNA-endoded structural subunits of complex I; CYB, the complex III structural subunit; CO genes, the three subunits of complex IV; ATP subunits, the two subunits of complex V; RNR1 and RNR2, 12S rRNA and 16S rRNA; Tx genes, the twenty-two tRNAs. Sequences of the genes are contiguous and even overlapping in the case of ND4L/ND4 and ATP8/ATP6. Mitochondrial and nuclear gene products whose mutation is associated with mitochondrial cardiomyopathy are highlighted in red. Model of complex I assembly, showing ND subunit entry points. The model unites previous knowledge and the new contributions from our group (Mol Cell Biol 2010). Perales-Clemente E, Fernández-Vizarra E, Acín-Pérez R, Movilla N, Bayona-Bafaluy MP, Moreno-Loshuertos R, Pérez-Martos A, Fernández-Silva P, Enríquez JA. Five entry points of the mitochondrially encoded subunits in mammalian complex I assembly. Mol Cell Biol (2010) 30: 3038-47 Fernández-Vizarra E, Ferrín G, Pérez-Martos A, Fernández-Silva P, Zeviani M, Enríquez JA. Isolation of mitochondria for biogenetical studies: An update. Mitochondrion (2010) 10: 253-62 Leigh-Brown S, Enriquez JA, Odom DT. Nuclear transcription factors in mammalian mitochondria. Genome Biol (2010) 11: 215 Charni S, de Bettignies G, Rathore MG, Aguiló JI, van den Elsen PJ, Haouzi D, Hipskind RA, Enriquez JA, Sanchez-Beato M, Pardo J, Anel A, Villalba M. Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway. J Immunol (2010) 185: 3498-503 Redondo-Horcajo M, Romero N, Martínez-Acedo P, Martínez-Ruiz A, Quijano C, Lourenço CF, Movilla N, Enríquez JA, Rodríguez- Pascual F, Rial E, Radi R, Vázquez J, Lamas S. Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide. Cardiovasc Res (2010) 87: 356-65 28
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Basic Research Departments - CNIC

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