Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Research output: Contribution to journalArticle

Authors

  • Karolina Y. Liu
  • Rakhee J. Mistry
  • Carlos A. Aguirre
  • Eirini S. Fasouli
  • Martin G. Thomas
  • And 3 others
  • Fábio Klamt
  • David B. Ramsden
  • Richard B. Parsons

Colleges, School and Institutes

External organisations

  • King's College London

Abstract

Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to 1-methylnicotinamide. We have previously shown that NNMT is significantly overexpressed in the brains of patients who have died of Parkinson's disease, and others have shown that NNMT is significantly overexpressed in a variety of diseases ranging from cancer to hepatic cirrhosis. In vitro overexpression has revealed many cytoprotective effects of NNMT, in particular increased complex I activity and ATP synthesis. Although this appears to be mediated by an increase in 1-methylnicotinamide production, the molecular mechanisms involved remain unclear. In the present study, we have investigated the role that sirtuins 1, 2 and 3, class III DNA deacetylase enzymes known to regulate mitochondrial energy production and cell cycle, have in mediating the effects of NNMT upon complex I activity. Expression of NNMT in SH-SY5Y human neuroblastoma cells, which have no endogenous expression of NNMT, significantly increased the expression of all three sirtuins. siRNA-mediated silencing of sirtuin 3 expression decreased complex I activity in NNMT-expressing SH-SY5Y cells to that observed in wild-type SH-SY5Y, and significantly reduced cellular ATP content also. These results demonstrate that sirtuin 3 is a key mediator of NNMT-induced complex I activity and ATP synthesis. These results further reinforce a central role for NNMT in the regulation of energy homeostasis and provide further mechanistic insight into the consequences of enhanced NNMT expression.

Details

Original languageEnglish
Pages (from-to)491-496
JournalBiochemical and Biophysical Research Communications
Volume467
Issue number3
Early online date8 Oct 2015
Publication statusPublished - 20 Nov 2015

Keywords

  • nicotinamide N-methyltransferase, Cancer, ATP, Bioenergetics, Complex I, Parkinson's disease