The mitochondrial bioenergetic phenotype for protection from cardiac ischemia in SUR2 mutant mice

Nitin T. Aggarwal, Danijel Pravdic, Elizabeth M. McNally, Zeljko J. Bosnjak, Nian Qing Shi, Jonathan C. Makielski

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The sulfonylurea receptor-2 (SUR2) is a subunit of ATP-sensitive potassium channels (K ATP) in heart. Mice with the SUR2 gene disrupted (SUR2m) are constitutively protected from ischemia-reperfusion (I/R) cardiac injury. This was surprising because K ATP, either sarcolemmal or mitochondrial or both, are thought to be important for cardioprotection. We hypothesized that SUR2m mice have an altered mitochondrial phenotype that protects against I/R. Mitochondrial membrane potential (Δψ m), tolerance to Ca 2+ load, and reactive oxygen species (ROS) generation were studied by fluorescence-based assays, and volumetric changes in response to K + were measured by light scattering in isolated mitochondria. For resting SUR2m mitochondria compared with wild type, the Δψ m was less polarized (46.1 ± 0.4 vs. 51.9 ± 0.6%), tolerance to Ca 2+ loading was increased (163 ± 2 vs. 116 ± 2 μM), and ROS generation was enhanced with complex I [8.5 ± 1.2 vs. 4.9 ± 0.2 arbitrary fluorescence units (afu)/s] or complex II (351 ± 51.3 vs. 166 ± 36.2 afu/s) substrates. SUR2m mitochondria had greater swelling in K + medium (30.2 ± 3.1%) compared with wild type (14.5 ± 0.6%), indicating greater K + influx. Additionally, Δψ m decreased and swelling increased in the absence of ATP in SUR2m, but the sensitivity to ATP was less compared with wild type. When the mitochondria were subjected to hypoxia-reoxygenation, the decrease in respiration rates and respiratory control index was less in SUR2m. Δψ m maintenance in the SUR2m intact myocytes was also more tolerant to metabolic inhibition. In conclusion, the cardioprotection observed in the SUR2m mice is associated with a protected mitochondrial phenotype resulting from enhanced K + conductance that partially dissipated Δψ m. These results have implications for possible SUR2 participation in mitochondrial K ATP.

Original languageEnglish (US)
Pages (from-to)H1884-H1890
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number6
DOIs
StatePublished - Dec 2010

Keywords

  • Adenosine 5-triphosphate-sensitive potassium channel
  • Cellular energetics
  • Ischemia
  • Ischemic-preconditioning
  • Mitochondria
  • Mitochondrial membrane potential
  • Mitochondrial respiration
  • Sulfonylurea receptor 2

ASJC Scopus subject areas

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

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