title: Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration.
abstract: The renin-angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the 'classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2). A combination of in vivo (rats, wild-type mice and knockout mice) and in vitro (primary mesencephalic cultures, dopaminergic neuron cell line cultures) experimental approaches (confocal microscopy, electron microscopy, laser capture microdissection, transfection of fluorescent-tagged receptors, treatments with fluorescent angiotensin, western blot, polymerase chain reaction, HPLC, mitochondrial respirometry and other functional assays) were used in the present study. We report the discovery of AT1 and AT2 receptors in brain mitochondria, particularly mitochondria of dopaminergic neurons. Activation of AT1 receptors in mitochondria regulates superoxide production, via Nox4, and increases respiration. Mitochondrial AT2 receptors are much more abundant and increase after treatment of cells with oxidative stress inducers, and produce, via nitric oxide, a decrease in mitochondrial respiration. Mitochondria from the nigral region of aged rats displayed altered expression of AT1 and AT2 receptors. AT2-mediated regulation of mitochondrial respiration represents an unrecognized primary line of defence against oxidative stress, which may be particularly important in neurons with increased levels of oxidative stress such as dopaminergic neurons. Altered expression of AT1 and AT2 receptors with aging may induce mitochondrial dysfunction, the main risk factor for neurodegeneration.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Rita
authors.initials: R
authors.lastname: Valenzuela
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Costa-Besada
authors.affiliation: Healing Foundation Centre, The University of Manchester, Manchester, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Iglesias-Gonzalez
authors.affiliation: Department of Pediatrics-Pediatric Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Perez-Costas
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Villar-Cheda
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garrido-Gil
authors.affiliation: Department of Surgery-Pediatric, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Melendez-Ferro
authors.affiliation: Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Soto-Otero
authors.affiliation: Neuroscience Department, Center for Applied Medical Research (CIMA, IdiSNA), University of Navarra, Pamplona, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: MITOVASC Institute, INSERM U1083, CNRS UMR6214, University of Angers, Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D019610:Cytoprotection; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005453:Fluorescence; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C485184:enhanced green fluorescent protein; C054562:yellow fluorescent protein, Bacteria; D013481:Superoxides; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat