Nitric oxide (NO) has a number of physiological and pathophysiological effects in the nervous system. One target of NO is the mitochondrion, where it inhibits respiration and ATP synthesis, which may contribute to NO-mediated neuronal injury. Our recent studies suggested that impaired mitochondrial function impairs mitochondrial trafficking, which could also contribute to neuronal injury. Here, we studied the effects of NO on mitochondrial movement and morphology in primary cultures of forebrain neurons using a mitochondrially targeted enhanced yellow fluorescent protein. NO produced by two NO donors, papa non-oate and diethylamine/NO complex, caused a rapid cessation of mitochondrial movement but did not alter morphology. Movement recovered after removal of NO. The effects of NO on movement were associated with dissipation of the mitochondrial membrane potential. Increasing cGMP levels using 8-bromoguanosine 3¢,5¢-cyclic monophosphate, did not mimic the effects on mitochondrial movement. Furthermore, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of NO-induced activation of soluble guanylate cyclase, did not block the effects of NO. Thus, neither increasing nor decreasing cGMP levels had an effect on mitochondrial movement. Based on these data, we conclude that NO is a novel modulator of mitochondrial trafficking in neurons, which may act through the inhibition of mitochondrial function. Nitric oxide (NO) is a second messenger and a neurotransmitter with diverse functions in the central nervous system. The signaling effects of NO are accomplished by several means. NO activates soluble guanylate cyclase (sGC), which results in the activation of cGMP-mediated signaling pathways (Garthwaite 1991;Bredt and Snyder 1992). It can also react with proteins, typically after reacting with superoxide to yield peroxynitrite (ONOO -), and such interactions may result in cytotoxicity (Beckman et al. 1996;Bolaños et al. 1997;Brown 1999). Mitochondria are also a target for NO, which can compete with O 2 to inhibit mitochondrial cytochrome c oxidase [complex IV (Brown 1999)]. ONOOmay also inhibit NADH-ubiquinone oxidoreductase (complex I), and these actions collectively inhibit mitochondrial respiration, perhaps contributing to neuronal injury (Brorson et al. 1999;Brown 1999).Mitochondria are a major source of ATP and are also important in maintaining neuronal Ca 2+ homeostasis (Nicholls and Budd 2000;Krieger and Duchen 2002). These organelles are dynamic entities, in that they undergo fission and fusion, replicate and travel over extended distances in neurons (Overly et al. 1996;Karbowski and Youle 2003
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