Activation of the cAMP cascade in human fibroblast cultures rescues the activity of oxidatively damaged complex I

A study of the relationship between cAMP/PKA-dependent phosphorylation and oxidative damage of subunits of complex I of the mitochondrial respiratory chain is presented. It is shown that, in fibroblast cultures, PKA-mediated phosphorylation of the NDUFS4 subunit of complex I rescues the activity of the oxidatively damaged complex. Evidence is presented showing that this effect is mediated by phosphorylation-dependent exchange of carbonylated NDUFS4 subunit in the assembled complex with the de novo synthesized subunit. These results indicate a potential use for β-adrenoceptor agonists in preventing/reversing the detrimental effects of oxidative stress in the mitochondrial respiratory system.

► Elevation of the cytosolic level of cAMP in human cell cultures, effected by the β-agonist isoproterenol, rescues the activity of oxidatively damaged complex I. ► cAMP exerts its rescue effect by promoting phosphorylation-dependent mitochondrial import of de novo synthesized NDUFS4 subunit and its assembly in the membrane-associated complex I. ► The results presented here indicate a potential use for β-adrenoceptor agonists in preventing/reversing detrimental effects of oxidative stress in the mitochondrial respiratory system.