Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes

Abstract

Calmodulin (CaM) and Ca(2+)/CaM-dependent protein kinase II (CaMKII) play important roles in the development of heart failure. In this study, we evaluated the effects of CaM on mitochondrial membrane potential (DeltaPsi(m)), permeability transition pore (mPTP) and the production of reactive oxygen species (ROS) in permeabilized myocytes; our findings are as follows. (1) CaM depolarized DeltaPsi(m) dose-dependently, but this was prevented by an inhibitor of CaM (W-7) or CaMKII (autocamtide 2-related inhibitory peptide (AIP)). (2) CaM accelerated calcein leakage from mitochondria, indicating the opening of mPTP, however this was prevented by AIP. (3) Cyclosporin A (an inhibitor of the mPTP) inhibited both CaM-induced DeltaPsi(m) depolarization and calcein leakage. (4) CaM increased mitochondrial ROS, which was related to DeltaPsi(m) depolarization and the opening of mPTP. (5) Chelating of cytosolic Ca(2+) by BAPTA, the depletion of SR Ca(2+) by thapsigargin (an inhibitor of SERCA) and the inhibition of mitochondrial Ca(2+) uniporter by Ru360 attenuated the effects of CaM on mitochondrial function. (6) CaM accelerated Ca(2+) extrusion from mitochondria. We conclude that CaM/CaMKII depolarized DeltaPsi(m) and opened mPTP by increasing ROS production, and these effects were strictly regulated by the local increase in cytosolic Ca(2+) concentration, initiated by Ca(2+) releases from the SR. In addition, CaM was involved in the regulation of mitochondrial Ca(2+) homeostasis.

Microtubule Disorganization Affects the Mitochondrial Permeability Transition Pore in Cardiac Myocytes

“…The SRreleased Ca 2+ dominates Ca 2+ concentration in the very restricted microdomain between mitochondria and SR, and influences mitochondrial Ca 2+ homeostasis. 18 Thus, it is possible that paclitaxel alters Ca 2+ release from the SR and subsequently affects the regulation of mPTP by altering mitochondrial Ca 2+ homeostasis.…”

Mitochondrial calcium overload is a key determinant in heart failure

“…Both increased and reduced mitochondrial Ca 2+ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca 2+ uptake has been associated with cellular dysfunction (14,20).…”

Mechanisms of non-apoptotic programmed cell death in diabetes and heart failure

“…These findings show that an important aspect of Nix-mediated cell death is programmed necrosis mediated by SR-mitochondrial crosstalk. As other reports have implicated cardiac myocyte or sarcoplasmic reticular calcium levels in cardiac injury and heart failure progression, [59][60][61] MTPT opening stimulated by reticular-mitochondrial calcium cross-talk may play a greater role than previously suspected in Figure 2. Schematic depiction of multiple Nix-induced pathways for cell death in heart failure.…”