title: The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress.
abstract: Uncoupling protein 3 (UCP3) is a member of the mitochondrial inner membrane carrier superfamily that modulates energy efficiency by catalyzing proton conductance and thus decreasing the production of superoxide anion. However, its role during oxidative stress and the underlying regulatory and molecular mechanisms remain poorly understood. We sought to investigate how UCP3 expression is regulated by oxidative stress and to evaluate the putative antioxidant role of this protein. H2O2 treatment increased UCP3 expression and the nuclear accumulation of the transcription factor Nrf2 in C2C12 and HL-1 cells. Nrf2 siRNA prevented H2O2-induced UCP3 expression, increasing oxidative stress and cell death. ChIP assays identified an antioxidant-response element (ARE) within the UCP3 promoter that bound Nrf2 after exposure to H2O2. Luciferase reporter experiments confirmed increased ARE activity in H2O2-treated HL-1 cells. Importantly, H2O2 increased the UCP3-mediated proton leak, suggesting a role for this protein in attenuating ROS-induced damage. Nrf2 nuclear accumulation and increased UCP3 protein were also detected in intact mouse heart subjected to a condition known to increase ROS generation. This is the first study to demonstrate that H2O2 augments UCP3 expression and it provides the first evidence of Nrf2 binding to the UCP3 promoter in response to oxidative challenge. These findings suggest that UCP3 functions as a member of the cellular antioxidant defense system that protects against oxidative stress in vivo. In conclusion, we have identified a novel regulatory process induced by an oxidative insult whereby the expression of the mitochondrial protein UCP3 is driven by the Nrf2 transcription factor, which decreases ROS production and prevents cell death.
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Anedda
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain.
authors.forename: Elia
authors.initials: E
authors.lastname: López-Bernardo
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain; Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IP), 28009 Madrid, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Acosta-Iborra
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: M
authors.initials: M
authors.lastname: Saadeh Suleiman
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain; Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IP), 28009 Madrid, Spain.
authors.forename: Manuel O
authors.initials: MO
authors.lastname: Landázuri
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain; Departamento de Biología Molecular, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain. Electronic address: susana.cadenas@uam.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Cadenas
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology; D001483:Base Sequence; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D015425:Myocardial Reperfusion; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D006861:Hydrogen Peroxide
keywords: Free radicals; Hydrogen peroxide; Ischemia–reperfusion; Langendorff perfusion system; Nrf2; Oxidative stress; Oxygen consumption; Respiration; UCP3