Identification of a Ryanodine Receptor in Rat Heart Mitochondria

  • Beutner G
  • Sharma V
  • Giovannucci D
 et al. 
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Abstract

Recent studies have shown that, in a wide variety of cells, mitochondria respond dynamically to physiological changes in cytosolic Ca(2+) concentrations ([Ca(2+)](c)). Mitochondrial Ca(2+) uptake occurs via a ruthenium red-sensitive calcium uniporter and a rapid mode of Ca(2+) uptake. Surprisingly, the molecular identity of these Ca(2+) transport proteins is still unknown. Using electron microscopy and Western blotting, we identified a ryanodine receptor in the inner mitochondrial membrane with a molecular mass of approximately 600 kDa in mitochondria isolated from the rat heart. [(3)H]Ryanodine binds to this mitochondrial ryanodine receptor with high affinity. This binding is modulated by Ca(2+) but not caffeine and is inhibited by Mg(2+) and ruthenium red in the assay medium. In the presence of ryanodine, Ca(2+) uptake into isolated heart mitochondria is suppressed. In addition, ryanodine inhibited mitochondrial swelling induced by Ca(2+) overload. This swelling effect was not observed when Ca(2+) was applied to the cytosolic fraction containing sarcoplasmic reticulum. These results are the first to identify a mitochondrial Ca(2+) transport protein that has characteristics similar to the ryanodine receptor. This mitochondrial ryanodine receptor is likely to play an essential role in the dynamic uptake of Ca(2+) into mitochondria during Ca(2+) oscillations.

Author-supplied keywords

  • Adenosine Triphosphate
  • Adenosine Triphosphate: metabolism
  • Animals
  • Calcium
  • Calcium-Transporting ATPases
  • Calcium-Transporting ATPases: antagonists & inhibi
  • Calcium-Transporting ATPases: metabolism
  • Calcium: metabolism
  • Cytosol
  • Cytosol: metabolism
  • Intracellular Membranes
  • Intracellular Membranes: physiology
  • Intracellular Membranes: ultrastructure
  • Kinetics
  • Microscopy, Immunoelectron
  • Mitochondria, Heart
  • Mitochondria, Heart: drug effects
  • Mitochondria, Heart: physiology
  • Mitochondria, Heart: ultrastructure
  • Mitochondrial Swelling
  • Mitochondrial Swelling: drug effects
  • Mitochondrial Swelling: physiology
  • Models, Biological
  • Radioligand Assay
  • Rats
  • Ryanodine
  • Ryanodine Receptor Calcium Release Channel
  • Ryanodine Receptor Calcium Release Channel: analys
  • Ryanodine Receptor Calcium Release Channel: physio
  • Ryanodine: pharmacokinetics
  • Ryanodine: pharmacology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPase

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Authors

  • G. Beutner

  • V. K. Sharma

  • D. R. Giovannucci

  • D. I. Yule

  • S.-S. Sheu

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