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Acidification reduces mitochondrial calcium uptake in rat cardiac mitochondria

¹Division of Cardiovascular Medicine, University of California-Davis, Davis 95616; and ²Cardiology Section, Department of Veteran Affairs Northern California Health Care System, Sacramento, California 95655

Submitted 12 April 2004 ; accepted in final form 29 July 2004

Cardiac ischemia-reperfusion (I/R) injury is accompanied by intracellular acidification that can lead to cytosolic and mitochondrial calcium overload. However, the effect of cytosolic acidification on mitochondrial pH (pH_m) and mitochondrial Ca²⁺ (Ca_m²⁺) handling is not well understood. In the present study, we tested the hypothesis that changes in pH_m during cytosolic acidification can modulate Ca_m²⁺handling in cardiac mitochondria. pH_m was measured in permeabilized rat ventricular myocytes with the use of confocal microscopy and the pH-sensitive fluorescent probe carboxyseminaphthorhodafluor-1. The contributions of the mitochondrial Na⁺/H⁺ exchanger (NHE_m) and the K⁺/H⁺ exchanger (KHE_m) to pH_m regulation were evaluated using acidification and recovery protocols to mimic the changes in pH observed during I/R. Ca_m²⁺transport in isolated mitochondria was measured using spectrophotometry and fluorimetry, and the mitochondrial membrane potential was measured using a tetraphenylphosphonium electrode. Cytosolic acidification (pH 6.8) resulted in acidification of mitochondria. The degree of mitochondrial acidification and recovery was found to be largely dependent on the activity of the KHE_m. However, the NHE_m was observed to contribute to the recovery of pH_m following acidification in K⁺-free solutions as well as the maintenance of pH_m during respiratory inhibition. Acidification resulted in mitochondrial depolarization and a decrease in the rate of net Ca_m²⁺uptake, whereas restoration of pH following acidification increased Ca_m²⁺uptake. These findings are consistent with an important role for cytosolic acidification in determining pH_m and Ca_m²⁺handling in cardiac mitochondria under conditions of Ca²⁺ overload. Consequently, interventions that alter pH_m can limit Ca_m²⁺overload and injury during I/R.

mitochondrial pH; mitochondrial calcium; sodium/hydrogen exchange; potassium/hydrogen exchange; mitochondrial membrane potential

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