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Am J Physiol Renal Physiol (January 29, 2002). doi:10.1152/ajprenal.00301.2001
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Articles in PresS, published online ahead of print January 28, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00301.2001
Submitted on September 25, 2001
Accepted on December 6, 2001

Mitochondrial dysfunction is an early event in high NaCl-induced apoptosis of mIMCD3 cells

Luis Michea1, Christian Combs2, Eugenia Peters1, Peter Andrews3, Natalia Dmitrieva1, and Maurice B Burg1*

1 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, Bethesda, MD, USA
2 Light Microscopy Imaging Facility, National Heart, Lung and Blood Institute, Bethesda, MD, USA
3 Department of Cell Biology, Georgetown University Medical Center, Washington, DC, USA

Raising osmolality to 700 mosmol/kg by adding NaCl rapidly kills most mIMCD3 cells, but they survive at 500. At 300 and 500 mosmol/kg NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 seconds to 30 minutes at 700 mosmol/kg the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased TMRM fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within one to six hours. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning one hour after raising osmolality to 700, but not to 500 mosmol/kg. General caspase activity and caspase-9 activity increase only after 6 hours at 700 mosmol/kg. The mitochondrial Bcl-2/Bax ratio decreases within 1 to 3 hours, but no cytochrome-c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kg does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis.




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