Reactive nitrogen and oxygen species (O2•−, H2O2, NO• and ONOO−) have been strongly implicated in the pathophysiology of neurodegenerative and mitochondrial diseases. In the present study, we examined the effects of nitrosative and/or nitrative stress generated by DETA-NO {(Z)-1-[2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate}, SIN-1 (3-morpholinosydnonimine hydrochloride) and SNP (sodium nitroprusside) on U87MG glioblastoma cybrids carrying wt (wild-type) and mutant [A3243G (Ala3243→Gly)] mtDNA (mitochondrial genome) from a patient suffering from MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The mutant cybrids had reduced activity of cytochrome c oxidase, significantly lower ATP level and decreased mitochondrial membrane potential. However, endogenous levels of reactive oxygen species were very similar in all cybrids regardless of whether they carried the mtDNA defects or not. Furthermore, the cybrids were insensitive to the nitrosative and/or nitrative stress produced by either DETA-NO or SIN-1 alone. Cytotoxicity, however, was observed in response to SNP treatment and a combination of SIN-1 and glucose-deprivation. The mutant cybrids were significantly more sensitive to these insults compared with the wt controls. Ultrastructural examination of dying cells revealed several characteristic features of autophagic cell death. We concluded that nitrosative and/or nitrative stress alone were insufficient to trigger cytotoxicity in these cells, but cell death was observed with a combination of metabolic and nitrative stress. The vulnerability of the cybrids to these types of injury correlated with the cellular energy status, which were compromised by the MELAS mutation.
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Research Article|
October 10 2005
Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation
Jagdeep K. Sandhu;
Jagdeep K. Sandhu
1
*Neurogenesis and Brain Repair Group, M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada K1A 0R6
1Correspondence may be addressed to either of the authors (email jagdeep.sandhu@nrc.ca and marianna.sikorska@nrc.ca).
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Caroline Sodja;
Caroline Sodja
*Neurogenesis and Brain Repair Group, M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada K1A 0R6
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Kevan Mcrae;
Kevan Mcrae
*Neurogenesis and Brain Repair Group, M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada K1A 0R6
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Yan Li;
Yan Li
*Neurogenesis and Brain Repair Group, M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada K1A 0R6
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Peter Rippstein;
Peter Rippstein
†Department of Pathology and Laboratory Medicine, The Ottawa Hospital-Civic Campus, Ottawa, ON, Canada K1Y 4E9
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Yau-Huei Wei;
Yau-Huei Wei
‡Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Boleslaw Lach;
Boleslaw Lach
§Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Fay Lee;
Fay Lee
∥Health Canada, Banting Research Center, Ottawa, ON, Canada K1A 0L2
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Septimiu Bucurescu;
Septimiu Bucurescu
¶Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5
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Mary-Ellen Harper;
Mary-Ellen Harper
¶Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5
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Marianna Sikorska
Marianna Sikorska
1
*Neurogenesis and Brain Repair Group, M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, Canada K1A 0R6
1Correspondence may be addressed to either of the authors (email jagdeep.sandhu@nrc.ca and marianna.sikorska@nrc.ca).
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Publisher: Portland Press Ltd
Received:
February 11 2005
Revision Received:
June 14 2005
Accepted:
June 21 2005
Accepted Manuscript online:
June 21 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 391 (2): 191–202.
Article history
Received:
February 11 2005
Revision Received:
June 14 2005
Accepted:
June 21 2005
Accepted Manuscript online:
June 21 2005
Citation
Jagdeep K. Sandhu, Caroline Sodja, Kevan Mcrae, Yan Li, Peter Rippstein, Yau-Huei Wei, Boleslaw Lach, Fay Lee, Septimiu Bucurescu, Mary-Ellen Harper, Marianna Sikorska; Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation. Biochem J 15 October 2005; 391 (2): 191–202. doi: https://doi.org/10.1042/BJ20050272
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