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


METHODS
Using 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.


RESULTS
The 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.


CONCLUSIONS
Signaling 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.
Department of Cardiovascular Biomedicine, National Institute of Cardiology, I.Ch., Juan Badiano No. 1, Colonia Sección XVI, Mexico 14080, DF, Mexico.
Sauri
S
Hernández-Reséndiz
Department of Cardiovascular Biomedicine, National Institute of Cardiology, I.Ch., Juan Badiano No. 1, Colonia Sección XVI, Mexico 14080, DF, Mexico. Electronic address: azazuetam@yahoo.com.
Cecilia
C
Zazueta
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057775:Ischemic Postconditioning; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3
Cardioprotection; Dilated cardiomyopathy; Mitochondrial ERK1/2; Postconditioning; Reperfusion; Signalosomes