title: Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity.
abstract: The fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1.
authors.affiliation: Servicio de Inmunología, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, 28006, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tello
authors.forename: Eduardo
authors.initials: E
authors.lastname: Balsa
authors.forename: Bárbara
authors.initials: B
authors.lastname: Acosta-Iborra
authors.forename: Esther
authors.initials: E
authors.lastname: Fuertes-Yebra
authors.forename: Ainara
authors.initials: A
authors.lastname: Elorza
authors.forename: Ángel
authors.initials: Á
authors.lastname: Ordóñez
authors.forename: María
authors.initials: M
authors.lastname: Corral-Escariz
authors.forename: Inés
authors.initials: I
authors.lastname: Soro
authors.forename: Elia
authors.initials: E
authors.lastname: López-Bernardo
authors.forename: Ester
authors.initials: E
authors.lastname: Perales-Clemente
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez-Ruiz
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Enríquez
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
authors.forename: Susana
authors.initials: S
authors.lastname: Cadenas
authors.forename: Manuel O
authors.initials: MO
authors.lastname: Landázuri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology*; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D008928:Mitochondria / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C571350:NDUFA4L2 protein, mouse; D042967:Electron Transport Complex I