Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function

Discovered in the cardiac sarcolemma, ATP-sensitive K+ (K-ATP) channels have more recently also been identified within the inner mitochondrial membrane. Yet the consequences of mitochondrial K-ATP channel activation 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 mitochondrial membrane potential, respiration, ATP generation, Ca2+ transport, and matrix volume. From a mitochondrial membrane potential of - 180 +/- 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 abolished 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 preloaded with Ca2+, an effect also dependent on extramitochondrial K+ concentration and sensitive to K-ATP channel blockade. In addition, K+ channel openers, cromakalim and pinacidil, increased matrix volume and released mitochondrial proteins, cytochrome and adenylate kinase. Thus, in isolated cardiac mitochondria, K-ATP channel openers depolarized the membrane, accelerated respiration, slowed ATP production, released accumulated Ca2+, produced swelling, and stimulated efflux of intermembrane proteins. These observations provide direct evidence far a role of mitochondrial K-ATP channels in regulating functions vital for the cardiac mitochondria.