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Nitric Oxide Synthesis Is Increased in Cybrid Cells with m.3243A>G Mutation
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de São Paulo, R. Pedro de Toledo, 781, São Paulo 04039-032, Brazil
Department of Neurology and Cell Biology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
* Author to whom correspondence should be addressed.
Received: 7 October 2012; in revised form: 10 December 2012 / Accepted: 14 December 2012 / Published: 24 December 2012
Abstract: Nitric oxide (NO) is a free radical and a signaling molecule in several pathways, produced by nitric oxide synthase (NOS) from the conversion of L-arginine to citrulline. Supplementation of L-arginine has been used to treat MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like syndrome), a mitochondrial disease caused by the m.3243A>G mutation. Low levels of serum arginine and endothelium dysfunction have been reported in MELAS and this treatment may increase NO in endothelial cells and promote vasodilation, decreasing cerebral ischemia and strokes. Although clinical benefits have been reported, little is known about NO synthesis in MELAS. In this study we found that osteosarcoma derived cybrid cells with high levels of m.3243A>G had increased nitrite, an NO metabolite, and increased intracellular NO, demonstrated by an NO fluorescent probe (DAF-FM). Muscle vessels from patients with the same mutation had increased staining in NADPH diaphorase, suggestive of increased NOS. These results indicate increased production of NO in cells harboring the m.3243A>G, however no nitrated protein was detected by Western blotting. Further studies are necessary to clarify the exact mechanisms of L-arginine effect to determine the appropriate clinical use of this drug therapy.
Keywords: mitochondria; nitric oxide; arginine; mitochondrial disease; mitochondrial DNA
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Gamba, J.; Gamba, L.T.; Rodrigues, G.S.; Kiyomoto, B.H.; Moraes, C.T.; Tengan, C.H. Nitric Oxide Synthesis Is Increased in Cybrid Cells with m.3243A>G Mutation. Int. J. Mol. Sci. 2013, 14, 394-410.
Gamba J, Gamba LT, Rodrigues GS, Kiyomoto BH, Moraes CT, Tengan CH. Nitric Oxide Synthesis Is Increased in Cybrid Cells with m.3243A>G Mutation. International Journal of Molecular Sciences. 2013; 14(1):394-410.
Gamba, Juliana; Gamba, Luana T.; Rodrigues, Gabriela S.; Kiyomoto, Beatriz H.; Moraes, Carlos T.; Tengan, Celia H. 2013. "Nitric Oxide Synthesis Is Increased in Cybrid Cells with m.3243A>G Mutation." Int. J. Mol. Sci. 14, no. 1: 394-410.