Mitochondrial nitric oxide signaling in synaptic plasticity and cell death

BOVERIS, A.; LORES ARNAIZ, S.; BUSTAMANTE, J.; CZERNICZYNIEC, A.

Nitric oxide, Cell Signaling and Gene Expression

Taylor & Francis Group

Lugar: Boca Ratón; Año: 2005; p. 29 - 44

Nitric oxide (NO) is a free radical, originally described as the endothelial relaxation factor, that is now considered as an intercellular messenger in physiological processes such as vasodilation and regulation of blood flow, neurotransmission, plaquetary agregation and inmunological response and as an intracellular regulator of mitochondrial respiration. Nitric oxide is synthesized from L-arginine, NADPH and O2, by the isoenzymes of the nitric oxide synthases (NOS) family. Three isoforms have been cloned and characterized: nNOS (NOS-1, neuronal NOS, originally identified as a constitutive form in neuronal tissue), iNOS (NOS-2, inducible NOS, originally identified as a form inducible by cytokines in macrophages and hepatocytes) and eNOS (NOS-3, endothelial NOS, originally identified as a constitutive form in vascular endothelial cells) (1-2). A large series of cellular enzymatic activities is affected by NO concentrations in the range of the physiological levels. Considering the diffusion properties of NO, that equals a few cell diameters (3), it is difficult to set the limits between intracellular and intercellular NO effects. Guanilate cyclase and cytochrome oxidase, in both cases with NO binding to an iron of the enzyme active center, are two metabolically important enzymes that are physiologically regulated by NO. In the first case, enzyme activation affords the mechanism for intercellular communication, and in the second case, the respiratory inhibition by NO generated intracellularly or in a neighbour cell appears as equally likely. The recognition of a NO synthase (NOS) localized in the mitochondria (mitochondrial NOS, mtNOS) prompted the concept of NO-mediated intraorganellar regulation of mitochondrial function. The intracellular localization of the NOS isoforms, with the already known bipolar distribution in mitochondria and cytosol (including in this latter the NOS isoforms of caveolae and plasma and endoplasmic reticulum membranes) and the cellular levels of substrates and Ca2+, constitute the molecular basis of the NO-dependent regulatory mechanisms. The cellular conditions in which NO diffuses from mitochondria to cytosol, as well as the conditions in which NO diffuses from cytosol to mitochondria are the current  questions for the complex processes of intracellular signaling that modulate the cell cycle and the cellular responses in almost all types of tissues.             In this review chapter, we discuss the processes and molecular mechanisms associated with neuronal plasticity and the cell death pathway in Ca2+-induced thymocyte apoptosis, two processes in which mitochondrial NO exhibits a regulatory role.