Winter Julia, Klumpe Inga, Heger Jacqueline, Rauch Ursula, Schultheiss Heinz-Peter, Landmesser Ulf, Dörner Andrea
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.
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.
Cell Signal. 2016 Jan;28(1):152-9. doi: 10.1016/j.cellsig.2015.11.002. Epub 2015 Nov 5.
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.
线粒体功能对细胞内信号传导的影响目前正在深入研究中。在这方面，我们分析了腺嘌呤核苷酸转位酶1（ANT1）对缺氧条件下细胞保护性生存信号传导的影响，ANT1可促进ADP和ATP在线粒体内膜的交换。ANT1过表达提高了缺氧心肌细胞的存活率。该效应与线粒体膜电位的稳定、半胱天冬酶3活性的抑制以及DNA片段化的减少有关。在缺氧的ANT1转基因（ANT1-TG）心肌细胞中，细胞保护性信号蛋白细胞外信号调节激酶1和2（ERK1/2）以及蛋白激酶B（AKT）的激活明显高于野生型心肌细胞。激酶激活与缺氧诱导因子1α的显著高表达相关，缺氧诱导因子1α可诱导糖酵解途径以稳定ATP生成。因此，ANT1-TG心肌细胞表现出乳酸脱氢酶更早、更强的激活以及更高的ATP含量。分别用ERK1/2和AKT激活抑制剂PD980559和三嗪核苷处理，消除了缺氧ANT1-TG心肌细胞的细胞保护作用。羧基苍术苷对ANT的抑制阻止了ERK1/2和AKT磷酸化的增加，并消除了缺氧ANT1-TG心肌细胞的细胞保护程序。总之，在缺氧的ANT1过表达心肌细胞中观察到的细胞保护作用涉及ANT1、ERK1/ERK2和AKT的激活以及这些激酶调节的生存过程诱导之间的相互依赖关系。
