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Role of Mitochondrial Na⁺ Concentration, Measured by CoroNa Red, in the Protection of Metabolically Inhibited MDCK Cells

Szilvia Baron^*,, Adrian Caplanusi^*,, Martin van de Ven^*, Mihai Radu, Sanda Despa^||, Ivo Lambrichts^¶, Marcel Ameloot^*, Paul Steels^* and Ilse Smets^*

^* Laboratory of Cell Physiology and ^¶ Laboratory of Histology, University Hasselt and transnationale Universiteit Limburg, Biomedisch Onderzoeksinstituut, Diepenbeek, Belgium; Department of Botany, Szeged University, Szeged, Hungary; Department of Medical Biochemistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Department of Health and Environmental Physics, Horia Hulubei National Institute for Physics and Nuclear Engineering, Bucharest, Romania; and ^|| Department of Physiology, Loyola University Chicago, Maywood, Illinois

Address correspondence to: Dr. Ilse Smets, MBW, Laboratory of Physiology, University Hasselt and transnationale Universiteit Limburg, Biomedisch Onderzoeksinstituut, Agoralaan Gebouw D, B-3590 Diepenbeek, Belgium. Phone: +32-11-26-85-35; Fax: +32-11-26-85-99; E-mail: ilse.smets{at}uhasselt.be

Received for publication January 19, 2005. Accepted for publication August 17, 2005.

In ischemic or hypoxic tissues, elevated cytosolic calcium levels can induce lethal processes. Mitochondria, besides the endoplasmic reticulum, play a key role in clearing excessive cytosolic Ca²⁺. In a previous study, it was suggested that the clearance of cytosolic Ca²⁺, after approximately 18 min of metabolic inhibition (MI) in renal epithelial cells, occurs via the reverse action of the mitochondrial Na⁺/Ca²⁺ exchanger (NCX). For further investigating the underlying mechanism, changes in the mitochondrial Na⁺ concentration ([Na⁺]_m) were monitored in metabolically inhibited MDCK cells. CoroNa Red, a sodium-sensitive fluorescence probe, was used to monitor [Na⁺]_m. In the first 15 min of MI, a twofold increase of [Na⁺]_m was observed reaching 113 ± 7 mM, whereas the cytosolic Na⁺ concentration ([Na⁺]_c) elevated threefold, to a level of 65 ± 6 mM. In the next 45 min of MI, [Na⁺]_m dropped to 91 ± 7 mM, whereas [Na⁺]_c further increased to 91 ± 4 mM. The striking rise in [Na⁺]_m is likely sufficient to sustain the driving force for mitochondrial Ca²⁺ uptake via the NCX. Furthermore, when CGP-37157, a specific inhibitor of the mitochondrial NCX, was applied during MI, the second-phase drop of [Na⁺]_m was completely abolished. The obtained results support the hypothesis that the mitochondrial NCX reverses after approximately 15 min of MI. Moreover, because the cellular homeostasis can recover after MI, the mitochondria likely protect MDCK cells from injury during MI by the reversal of the mitochondrial NCX. This study is the first to report [Na⁺]_m measurements in nonpermeabilized living cells.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673