Mitochondrial nitric oxide synthase: a masterpiece of metabolic adaptation, cell growth, transformation, and death (original) (raw)
Related papers
Indian Journal of Clinical Biochemistry, 2011
Nitric oxide (NO) a free radical having both cytoprotective as well as tumor promoting agent is formed from L-arginine by converting it to L-citrulline via nitric oxide synthase enzymes. The reaction product of nitric oxide with superoxide generates potent oxidizing agent, peroxynitrite which is the main mediator of tissue and cellular injury. Peroxynitrite is reactive towards many biomolecules which includes amino acids, nucleic acid bases; metal containing compounds, etc. NO metabolites may play a key role in mediating many of the genotoxic/ carcinogenic effects as DNA damage, protein or lipid modification, etc. The basic reactions of nitric oxide can be divided as direct effect of the radical where it alone plays a role in either damaging or protecting the cell milieu and an indirect effect in which the byproducts of nitric oxide formed by convergence of two independent radical generating pathways play the role in biological reactions which mainly involve oxidative and nitrosative stress. Nitric oxide is also capable of directly interacting with mitochondria through inhibition of respiration or by permeability transition. Reaction of nitric oxide with metal ions include its direct interaction with the metals or with oxo complexes thereby reducing them to lower valent state. Excessive production of nitric oxide can be studied by inhibiting the synthetic pathway of nitric oxide using both selective or specific nitric oxide synthase inhibitor or nonselective nitric oxide synthase inhibitor with respect to isoforms of nitric oxide.
Mitochondrial nitric oxide synthase
Frontiers in Bioscience, 2007
Mitochondria produce nitric oxide (NO) through a Ca 2Csensitive mitochondrial NO synthase (mtNOS). The NO produced by mtNOS regulates mitochondrial oxygen consumption and transmembrane potential via a reversible reaction with cytochrome c oxidase. The reaction of this NO with superoxide anion yields peroxynitrite, which irreversibly modifies susceptible targets within mitochondria and induces oxidative and/or nitrative stress. In this article, we review the current understanding of the roles of mtNOS as a crucial biochemical regulator of mitochondrial functions and attempt to reconcile apparent discrepancies in the literature on mtNOS. Discovery of mitochondrial nitric oxide synthase The discovery that the endothelium-derived relaxing factor is nitric oxide (NO) [1] opened new horizons in biomedical research. The cellular synthesis of NO is catalyzed by NO synthase (NOS) isozymes, three of which are well characterized. Although expression of these enzymes is not tissue specific, they are referred to as neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Each isozyme consumes L-arginine, produces equal amounts of NO and L-citrulline, and requires Ca 2C-calmodulin for activity. The activity of eNOS and nNOS are regulated tightly by alterations in Ca 2C status but, because iNOS forms a complex with calmodulin at very low concentrations of Ca 2C , its activity is not regulated by Ca 2C alterations. NO exerts a broad spectrum of functions in several system, including the cardiovascular system, PNS, CNS and immune system. These functions are mediated through the reactions of NO with targets that include hemoproteins, thiols and superoxide anions. Mitochondria possess several hemoproteins (e.g. cytochrome c oxidase), thiols (e.g. glutathione) and cysteine-containing proteins, and they are major cellular sources of superoxide anion. Consequently, mitochondria are important targets of NO and contribute to several of the biological functions of NO [2]. Several laboratories have addressed the possibility that NOS is present in mitochondria. The cross-reaction of mitochondria with antibodies to Ca 2C-sensitive eNOS was reported almost simultaneously by two laboratories. In rats, mitochondria from skeletal muscle fibers from the diaphragm [3], non-synaptosomal brain [4], and heart, skeletal muscle and kidney [5] cross-react with eNOS antibodies. Other laboratories also report an association