The mitochondrial bioenergetic phenotype for protection from cardiac ischemia in SUR2 mutant mice. Am J Physiol Heart Circ Physiol 2010 Dec;299(6):H1884-90
Date
10/12/2010Pubmed ID
20935152Pubmed Central ID
PMC3006279DOI
10.1152/ajpheart.00363.2010Scopus ID
2-s2.0-78649719810 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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).
Author List
Aggarwal NT, Pravdic D, McNally EM, Bosnjak ZJ, Shi NQ, Makielski JCMESH terms used to index this publication - Major topics in bold
ATP-Binding Cassette TransportersAdenosine Triphosphate
Animals
Calcium
Cell Hypoxia
Cell Respiration
Energy Metabolism
Genotype
Light
Male
Membrane Potential, Mitochondrial
Mice
Mice, Mutant Strains
Mitochondria, Heart
Mitochondrial Swelling
Myocardial Reperfusion Injury
Myocytes, Cardiac
Phenotype
Potassium
Potassium Channels
Potassium Channels, Inwardly Rectifying
Reactive Oxygen Species
Receptors, Drug
Scattering, Radiation
Spectrometry, Fluorescence
Sulfonylurea Receptors
Time Factors
