title: Adenine nucleotide translocase 1 overexpression protects cardiomyocytes against hypoxia via increased ERK1/2 and AKT activation.
abstract: The influence of mitochondrial function on intracellular signalling is currently under intense investigation. In this regard, we analysed the effect of adenine nucleotide translocase 1 (ANT1), which facilitates the exchange of ADP and ATP across the mitochondrial membrane, on cell-protective survival signalling under hypoxia. ANT1 overexpression enhanced the survival rate in hypoxic cardiomyocytes. The effect was related to stabilization of the mitochondrial membrane potential, suppression of caspase 3 activity, and a reduction in DNA fragmentation. Activation of the cell-protective signalling proteins extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (AKT) was substantially higher in hypoxic ANT1-transgenic (ANT1-TG) cardiomyocytes than in wild-type cardiomyocytes. Kinase activation was associated with significantly higher expression of hypoxia-inducible factor 1α, which induces glycolytic pathway to stabilize ATP production. Accordingly, ANT1-TG cardiomyocytes exhibited earlier and stronger activation of lactate dehydrogenase and a higher ATP content. Treatment with PD980559 and triciribine, inhibitors of ERK1/2 and AKT activation, respectively, abolished cell protection in hypoxic ANT1-TG cardiomyocytes. Inhibition of ANT by carboxyatractyloside prevented the increase in ERK1/2 and AKT phosphorylation and eliminated the cell protective program in hypoxic ANT1-TG cardiomyocytes. In conclusion, the cytoprotective effect observed in hypoxic ANT1-overexpressing cardiomyocytes involves an interdependence between ANT1, activation of ERK1/ERK2 and AKT, and induction of the survival processes regulated by these kinases.
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany; Institute of Chemistry and Biochemistry, Structural Biochemistry, Free University Berlin, Takustr. 6, 14195, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Winter
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany; Institute of Biochemistry, Free University Berlin, Thielallee 63, 14195, Berlin, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Klumpe
authors.affiliation: Institute of Physiology, Justus-Liebig-University, Aulweg 129, 35392 Giessen, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Heger
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rauch
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. Electronic address: andrea.doerner@charite.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dörner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D020011:Protective Agents; D000226:Mitochondrial ADP, ATP Translocases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: AKT; Adenine nucleotide translocase; ERK1/2; Hypoxia; Mitochondria; Survival signalling