NNMT (nicotinamide N-methyltransferase, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson's disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell line, a tumour-derived human dopaminergic neuroblastoma cell line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP/ADP ratio and Complex I activity, and a reduction in the degradation of the NDUFS3 [NADH dehydrogenase (ubiquinone) iron–sulfur protein 3] subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-methylnicotinamide, suggesting that 1-methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone by reversing their effects upon ATP synthesis, the ATP/ADP ratio, Complex I activity and the NDUFS3 subunit. The results of the present study raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, the results of the present study also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
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Research Article|
April 27 2011
The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors
Richard B. Parsons;
Richard B. Parsons
1
*King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, U.K.
1To whom correspondence should be addressed (email richard.parsons@kcl.ac.uk).
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Shylesh Aravindan;
Shylesh Aravindan
†St George's, University of London, Division of Basic Medical Sciences, Cranmer Terrace, London SW17 0RE, U.K.
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Anusha Kadampeswaran;
Anusha Kadampeswaran
†St George's, University of London, Division of Basic Medical Sciences, Cranmer Terrace, London SW17 0RE, U.K.
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Emily A. Evans;
Emily A. Evans
†St George's, University of London, Division of Basic Medical Sciences, Cranmer Terrace, London SW17 0RE, U.K.
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Kanwaljeet K. Sandhu;
Kanwaljeet K. Sandhu
†St George's, University of London, Division of Basic Medical Sciences, Cranmer Terrace, London SW17 0RE, U.K.
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Elizabeth R. Levy;
Elizabeth R. Levy
*King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, U.K.
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Martin G. Thomas;
Martin G. Thomas
*King's College London, Institute of Pharmaceutical Science, 150 Stamford Street, London SE1 9NH, U.K.
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Brian M. Austen;
Brian M. Austen
†St George's, University of London, Division of Basic Medical Sciences, Cranmer Terrace, London SW17 0RE, U.K.
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David B. Ramsden
David B. Ramsden
‡The University of Birmingham, Department of Medicine, Edgbaston, Birmingham B15 2TH, U.K.
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Publisher: Portland Press Ltd
Received:
October 15 2010
Revision Received:
February 22 2011
Accepted:
February 25 2011
Accepted Manuscript online:
February 25 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 436 (1): 145–155.
Article history
Received:
October 15 2010
Revision Received:
February 22 2011
Accepted:
February 25 2011
Accepted Manuscript online:
February 25 2011
Citation
Richard B. Parsons, Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Elizabeth R. Levy, Martin G. Thomas, Brian M. Austen, David B. Ramsden; The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors. Biochem J 15 May 2011; 436 (1): 145–155. doi: https://doi.org/10.1042/BJ20101685
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