CONICET | Buscador de Institutos y Recursos Humanos

Phylogenetic studies had shown that evolution of mitochondria occurred in parallel with the maturation of kinases implicated in the processes of growth and delimitation of the final size of modern organisms. In the last years, different reports confirmed that MAPKs, Akt, PKA and PKC are present in mitochondria, particularly in the intermembrane space and inner membrane where they meet mitochondrial constitutive upstream activators. Although a priori phosphorylation is the apparent aim of kinase translocation to the organelles, new perspectives indicate that kinase activation depends on redox status as determined by the mitochondrial production of oxygen species. In this way, we observed that the degree of mitochondrial oxidation of ERK Cys38 and Cys214 discriminates the kinase to be phosphorylated or unphosphorylated at least in one of the target residues and thereby, it determines the fate in terms of translocation to the nuclear compartment and proliferation or accumulation in mitochondria and arrest; in accord, tumor cells with reduced production of oxygen species are unable to arrest cell growth and remain in an undefined proliferative state. In addition, active ERK and Akt have antiapoptotic effects by phosphorylation of mitochondrial Bcl-2 and Bcl-xL. Otherwise, PKC protects cell and mitochondria from ischemic death by interacting with mitochondrial nitric oxide and opening the mitoK+ ATP channels. In this case, K+ entrance to mitochondria and nitric oxide itself promote a discrete burst of hydrogen peroxide that activates PKC and Akt. It is concluded that the interactions between kinases and mitochondria control a significant group of cell signaling pathways and participate in the modulation of dissimilar functions as cell proliferation and arrest, insulin signaling, tissue protection, tumorigenesis and cancer progression.