RT Journal Article
SR Electronic
T1 Regulation of Mitochondrial poly(ADP-ribose) Polymerase Activation by the β-adrenoceptor / cAMP / Protein Kinase A Axis During Oxidative Stress
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.094318
DO 10.1124/mol.114.094318
A1 Attila Brunyanszki
A1 Gabor Olah
A1 Ciro Coletta
A1 Bartosz Szczesny
A1 Csaba Szabo
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/07/28/mol.114.094318.abstract
AB Here we investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cAMP / protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 min) 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. β-adrenoceptor blockade with propranolol or inhibition of its downstream cAMP / PKA signaling attenuated, while β-adrenoceptor agonists and cAMP / PKA activators enhanced the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylates recombinant PARP1 on serines 465 (in the auto-modification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the β-adrenergic receptor / cAMP / PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes, during 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 β-adrenoceptor / cAMP / PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.