MITOCHONDRIAL ATP-SENSITIVE K-FUNCTION( CHANNELS MODULATE CARDIAC MITOCHONDRIAL)

Discovered in the cardiac sarcolemma, ATP-sensitive K+ (K-ATP) channel s have more recently also been identified within the inner mitochondri al membrane. Yet the consequences of mitochondrial K-ATP channel activ ation on mitochondrial function remain partially documented. Therefore , we isolated mitochondria from rat hearts and used K+ channel openers to examine the effect of mitochondrial K-ATP channel opening on mitoc hondrial membrane potential, respiration, ATP generation, Ca2+ transpo rt, and matrix volume. From a mitochondrial membrane potential of - 18 0 +/- 15 mV, K+ channel openers, pinacidil (100 mu M), cromakalim (25 mu M), and levcromakalim (20 mu M), induced membrane depolarization by 10 +/- 7, 25 +/- 9, and 24 +/- 10 mV, respectively. This effect was a bolished by removal of extramitochondrial K+ or application of a K-ATP channel blocker K+ channel opener-induced membrane depolarization was associated with an increase in the rate of mitochondrial respiration and a decrease in the rate of mitochondrial ATP synthesis. Furthermore , treatment with a K+ channel opener released Ca2+ from mitochondria p reloaded with Ca2+, an effect also dependent on extramitochondrial Kconcentration and sensitive to K-ATP channel blockade. In addition, K channel openers, cromakalim and pinacidil, increased matrix volume an d released mitochondrial proteins, cytochrome and adenylate kinase. Th us, in isolated cardiac mitochondria, K-ATP channel openers depolarize d the membrane, accelerated respiration, slowed ATP production, releas ed accumulated Ca2+, produced swelling, and stimulated efflux of inter membrane proteins. These observations provide direct evidence far a ro le of mitochondrial K-ATP channels in regulating functions vital for t he cardiac mitochondria.