K+-dependent regulation of matrix volume improves mitochondrial function under conditions mimicking ischemia-reperfusion

• Published in: American journal of physiology. Heart and circulatory physiology 2005-07, Vol.289 (1), p.H66-H77
• Main Authors: Korge, Paavo, Honda, Henry M, Weiss, James N
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - metabolism; Adenosine Diphosphate - pharmacology; Animals; Caproates - pharmacology; Cell Hypoxia; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Magnesium - pharmacology; Membrane Potentials - drug effects; Mitochondria, Heart - metabolism; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Oxygen - pharmacology; Oxygen Consumption - drug effects; Phosphorylation - drug effects; Potassium - metabolism; Rabbits
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01296.2004

University of California-Los Angeles Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, and Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California Submitted 23 December 2004 ; accepted in final form 10 March 2005 To delineate the role of mitochondrial K + fluxes in cardioprotection, we investigated the effect of extramitochondrial K + on the ability of mitochondria to support membrane potential ( ), regulate matrix volume, consume oxygen, and phosphorylate ADP under conditions mimicking key elements of ischemia-reperfusion. Isolated energized mitochondria responded to ADP addition with depolarization, increased O 2 consumption, and matrix shrinkage. The time required for full recovery of , signaling the completion of ADP phosphorylation, was used to evaluate the rate of ATP synthesis during repeated ADP pulses. In mitochondria with a decreased ability to support , the rate of ADP phosphorylation was significantly improved by extramitochondrial K + > Na + > Li + , especially at higher buffer osmolarity, which promotes matrix shrinkage. K + -induced improvement in recovery after ADP pulses was accompanied by more rapid and complete matrix volume recovery and enhanced O 2 consumption. Manipulations expected to affect matrix swelling by regulating K + fluxes or water distribution indicate that matrix volume regulation by external factors becomes increasingly important in mitochondria with decreased ability to support in the face of a high ADP load. Under these conditions, opening of K + influx pathways improved mitochondrial function and delayed failure. This may be an important factor in the mechanism of diaxozide-induced cardioprotection. mitochondria; matrix swelling; shrinkage; hypoxia; reoxygenation Address for reprint requests and other correspondence: P. Korge, Cardiovascular Research Laboratory, 3645 MRL Bldg., 675 Charles Young Dr. S., David Geffen School of Medicine, Univ. of California, Los Angeles, CA 90095 (E-mail: pkorge{at}mednet.ucla.edu )