Mitochondria in the redox modularity of cell signaling

CARRERAS MC, ANTICO ARCIUCH VG, PODEROSO JJ

Santiago, Chile

Congreso; VI Meeting of the SFRBM- South American Group; 2009

SFRBM- South American Group

Activation of kinases by a redox challenge (i.e. MAPKs, Akt, PKC or PKA) follows a particular modular behavior, as given by differential phosphorylation of upstream and downstream cognates. This condition was explored in in vivo models, in isolated mitochondria ex vivo, and with pure recombinant kinases. In the first case, we followed the redox changes imposed by progressive increase of mtNOS that is accompanied by increase of H2O2 in rat liver and brain development. Redox transition determined sequential activation of ERK1/2 in the proliferation of the organs and inactivation of ERK1/2 and activation of proapoptotic p38 MAPK at growth arrest. Similarly and depending on the thyroid status, T3 or T4 reduces mtNOS and H2O2 in liver and muscle and stimulates phosphorylation of ERK1/2 and cyclin D1 and D2 and cell proliferation, while low T3 activates p38 MAPK limiting growth and size in the phenotype of hypothyroidism. In general, the process of activation of MAPKs was thought to occur in a two compartmental way, from cytosol to nucleus. However and at different redox status, we and others recently reported that a transient mitochondrial passage alternatively contributes to activation or inactivation of kinases regulating their traffic to nucleus. At low H2O2, recombinant ERK1/2 enters to mitochondria and becomes promptly phosphorylated and translocated to nucleus while at high H2O2 remains inactive in the organelles. We observed that at low H2O2 this behavior depends on posttranslational changes mainly oxidation of specific cysteines like Cys38 and Cys214 that increase ERK1/2 phosphorylation by MEK1/2 in mitochondria. Therefore, redox effects drive cell fate and kinase oxidation by increasing NO and H2O2 in the mitochondrial milieu.