PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling

AimsThe molecular mechanism(s) by which extracellular signal-regulated kinase 1/2 (ERK1/2) and other kinases communicate with downstream targets have not been fully determined. Multiprotein signaling complexes undergoing spatiotemporal redistribution may enhance their interaction with effector proteins promoting cardioprotective response. Particularly, it has been proposed that some active kinases in association with caveolae may converge into mitochondria. Therefore, in this study we investigate if PHO-ERK1/2 interaction with mitochondria may provide a mechanistic link in the regulation of these organelles in cardioprotective signaling.Main methodsUsing a model of dilated cardiomyopathy followed by ischemia–reperfusion injury, we determined ERK1/2 signaling at the level of mitochondria and evaluated its effect on the permeability transition pore.Key findingsThe most important finding of the present study is that, under cardioprotective conditions, a subpopulation of activated ERK1/2 was directed to the mitochondrial membranes through vesicular trafficking, concurring with increased phosphorylation of mitochondrial proteins and inhibition of the mitochondrial permeability transition pore opening. In addition, our results suggest that vesicles enriched with caveolin-3 could form structures that may drive ERK1/2, GSK3β and Akt to mitochondria.SignificanceSignaling complexes including PHO-ERK, PHO-Akt, PHO-eNOS and caveolin-3 contribute to cardioprotection by directly targeting the mitochondrial proteome and regulating the opening of the permeability transition pore in this model.

Postconditioning conferred cardioprotection by signaling molecules in hearts with dilated cardiomyopathy (DCM hearts). The interaction of adenosine and other GPCR agonists induces the formation of signaling platforms (signaling molecules) that phosphorylate mitochondrial proteins producing cardioprotection.Figure optionsDownload high-quality image (257 K)Download as PowerPoint slide