Dynamic modulation of Ca2+ sparks by mitochondrial oscillations in isolated guinea pig cardiomyocytes under oxidative stress

Academic Article


  • Local control of Ca -induced Ca release (CICR) depends on the spatial organization of L-type Ca channels and ryanodine receptors (RyR) in the dyad. Analogously, Ca uptake by mitochondria is facilitated by their close proximity to the Ca release sites, a process required for stimulating oxidative phosphorylation during changes in work. Mitochondrial feedback on CICR is less well understood. Since mitochondria are a primary source of reactive oxygen species (ROS), they could potentially influence the cytosolic redox state, in turn altering RyR open probability. We have shown that self-sustained oscillations in mitochondrial inner membrane potential (ΔΨ ), NADH, ROS, and reduced glutathione (GSH) can be triggered by a laser flash in cardiomyocytes. Here, we employ this method to directly examine how acute changes in energy state dynamically influence resting Ca spark occurrence and properties. Two-photon laser scanning microscopy was used to monitor cytosolic Ca (or ROS), ΔΨ , and NADH (or GSH) simultaneously in isolated guinea pig cardiomyocytes. Resting Ca spark frequency increased with each ΔΨ depolarization and decreased with ΔΨ repolarization without affecting Ca spark amplitude or time-to-peak. Stabilization of mitochondrial energetics by pretreatment with the superoxide scavenger TMPyP, or by acute addition of 4'-chlorodiazepam, a mitochondrial benzodiazepine receptor antagonist that blocks the inner membrane anion channel, prevented or reversed, respectively, the increased spark frequency. Cyclosporine A did not block the ΔΨ oscillations or prevent Ca spark modulation by ΔΨ . The results support the hypothesis that mitochondria exert an influential role on the redox environment of the Ca handling subsystem, with mechanistic implications for the pathophysiology of cardiac disease. © 2011 Elsevier Ltd. 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ m m m m m m
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Zhou L; Aon MA; Liu T; O'Rourke B
  • Start Page

  • 632
  • End Page

  • 639
  • Volume

  • 51
  • Issue

  • 5