Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function

Ekshon L. Holmuhamedov, Sofija Jovanović, Petras P. Dzeja, Aleksandar Jovanović, Andre Terzic

Research output: Contribution to journalArticle

318 Scopus citations

Abstract

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 μM), cromakalim (25 μM), and levcromakalim (20 μM), 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 KATe channel blockade. In addition, K+ channel openers, cromakalim and pinacidil, increased matrix volume and released mitochondrial proteins, cytochrome c 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 for a role of mitochondrial K(ATP) channels in regulating functions vital for the cardiac mitochondria.

Original languageEnglish (US)
Pages (from-to)H1567-H1576
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume275
Issue number5 44-5
DOIs
StatePublished - Nov 1998

Keywords

  • Calcium
  • Heart
  • Mitochondria
  • Potassium channel openers

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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