Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by the β-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress
Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by the β-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress
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DOI：
10.1124/mol.114.094318
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发表时间：
2014-10-01
影响因子：
3.6
通讯作者：
Szabo, Csaba
中科院分区：
文献类型：
--
作者：
Brunyanszki, Attila;Olah, Gabor;Szabo, Csaba
我们研究了U937单核细胞氧化应激过程中环磷酸腺苷(CAMP)/蛋白激酶A(PKA)系统对线粒体多聚(ADP-核糖)聚合酶1(PARP1)的调节作用。氧化应激导致早期(10分钟)线粒体DNA损伤，并伴随着线粒体中PARP1的激活。在这些早期事件之后，线粒体氧化剂的产生和核PARP1的激活(到6小时)逐渐增加。这些过程导致线粒体功能受损，最终导致混合型(坏死/凋亡)细胞死亡。心得安阻断β受体或抑制其下游cAMP/PKA信号转导减弱，而β受体激动剂和cAMP/PKA激动剂增强氧化剂介导的PARP1激活。在cAMP存在的情况下，重组PKA直接磷酸化重组PARP1的丝氨酸465(在自化区域)和782和785(都在催化区域)。抑制β-肾上腺素能受体/cAMP/PKA轴对氧化剂介导的细胞损伤具有保护作用。在细菌脂多糖(LPS)诱导的小鼠全身炎症过程中，心得安也能抑制外周血白细胞中PARP1的激活。我们的结论是，线粒体PARP1的激活是氧化剂诱导的细胞死亡的早期、活跃的参与者，该过程受β-肾上腺素受体/cAMP/PKA轴的控制，通过PARP1的磷酸化来调节PARP1的活性。
We investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 minutes) mitochondrial DNA damage, and concomitant activation of PARP1 in the mitochondria. These early events were followed by a progressive mitochondrial oxidant production and nuclear PARP1 activation (by 6 hours). These processes led to a functional impairment of mitochondria, culminating in cell death of mixed (necrotic/apoptotic) type. beta-Adrenoceptor blockade with propranolol or inhibition of its downstream cAMP/PKA signaling attenuated, while beta-adrenoceptor agonists and cAMP/PKA activators enhanced, the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the beta-adrenergic receptor/cAMP/PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes during bacterial lipopolysaccharide (LPS)-induced systemic inflammation in mice. We conclude that the activation of mitochondrial PARP1 is an early, active participant in oxidant-induced cell death, which is under the control of beta-adrenoceptor/cAMP/PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.