title: 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.
authors.affiliation: Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Higashi-ward, Hamamatsu, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Odagiri
authors.forename: Hideki
authors.initials: H
authors.lastname: Katoh
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kawashima
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hayato
authors.initials: H
authors.lastname: Ohtani
authors.forename: Masao
authors.initials: M
authors.lastname: Saotome
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Urushida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi