1. ¹Department of Biochemistry, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2. ²Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
3. ³National University Medical Institutes, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
4. ⁴Department of Physiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Correspondence: M-V Clément, The Yong Loo Lin School of Medicine, Department of Biochemistry, National University of Singapore, 8 Medical Drive, MD7, Singapore 117 597, Singapore. Tel: +65-6874-7985; Fax: +65-6779-1453; E-mail: bchmvc@nus.edu.sg

Received 28 December 2004; Revised 6 July 2005; Accepted 11 August 2005; Published online 23 September 2005.

Abstract

We have previously demonstrated that a slight increase in intracellular superoxide (O₂^-) anion confers resistance to death stimuli. Using pharmacological and molecular approaches to manipulate intracellular O₂^-, here we report that an increase in intracellular O₂^- anion induces Na⁺/H⁺ exchanger 1 (NHE-1) gene promoter activity resulting in increased NHE-1 protein expression, which strongly correlates with the resistance of cells to death stimuli. In contrast, exposure to exogenous hydrogen peroxide suppressed NHE-1 promoter activity and gene expression, and increased cell sensitivity to death triggers. Furthermore, the increase in cell sensitivity to death upon downregulation of NHE-1 gene expression correlates with reduced capacity of cells to recover from an acid load, while survival upon overexpression of NHE-1 appears independent of its pump activity. These findings indicate that NHE-1 is a redox-regulated gene, and provide a novel intracellular target for the redox control of cell death sensitivity.