Effects of mitochondrial uncoupling on Ca(2+) signaling during excitation-contraction coupling in atrial myocytes Journal Article


Authors: Zima, A. V.; Pabbidi, M. R.; Lipsius, S. L.; Blatter, L. A.
Article Title: Effects of mitochondrial uncoupling on Ca(2+) signaling during excitation-contraction coupling in atrial myocytes
Abstract: Mitochondria play an important role in intracellular Ca(2+) concentration ([Ca(2+)]i) regulation in the heart. We studied sarcoplasmic reticulum (SR) Ca(2+) release in cat atrial myocytes during depolarization of mitochondrial membrane potential (DeltaPsim) induced by the protonophore FCCP. FCCP caused an initial decrease of action potential-induced Ca(2+) transient amplitude and frequency of spontaneous Ca(2+) waves followed by partial recovery despite partially depleted SR Ca(2+) stores. In the presence of oligomycin, FCCP only exerted a stimulatory effect on Ca(2+) transients and Ca(2+) wave frequency, suggesting that the inhibitory effect of FCCP was mediated by ATP consumption through reverse-mode operation of mitochondrial F1F0-ATPase. DeltaPsim depolarization was accompanied by cytosolic acidification, increases of diastolic [Ca(2+)]i, intracellular Na(+) concentration ([Na(+)]i), and intracellular Mg(2+) concentration ([Mg(2+)]i), and a decrease of intracellular ATP concentration ([ATP]i); however, glycolytic ATP production partially compensated for the exhaustion of mitochondrial ATP supplies. In conclusion, the initial inhibition of Ca(2+) transients and waves resulted from suppression of ryanodine receptor SR Ca(2+) release channel activity by a decrease in [ATP], an increase of [Mg(2+)]i, and cytoplasmic acidification. The later stimulation resulted from reduced mitochondrial Ca(2+) buffering and cytosolic Na(+) and Ca(2+) accumulation, leading to enhanced Ca(2+)-induced Ca(2+) release and spontaneous Ca(2+) release in the form of Ca(2+) waves. DeltaPsim depolarization and the ensuing consequences of mitochondrial uncoupling observed here (intracellular acidification, decrease of [ATP]i, increase of [Na(+)]i and [Mg(2+)]i, and Ca(2+) overload) are hallmarks of ischemia. These findings may therefore provide insight into the consequences of mitochondrial uncoupling for ion homeostasis, SR Ca(2+) release, and excitation-contraction coupling in ischemia at the cellular and subcellular level.
Journal Title: American Journal of Physiology - Heart Circulatory Physiology
Volume: 304
Issue: 7
ISSN: 0363-6135
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: H983
End Page: 93
Language: eng
DOI/URL:
Notes: ID: 13044; GR: HL-079038/HL/NHLBI NIH HHS/United States; GR: HL-101235/HL/NHLBI NIH HHS/United States; GR: HL-62231/HL/NHLBI NIH HHS/United States; GR: HL-80101/HL/NHLBI NIH HHS/United States; JID: 100901228; OID: NLM: PMC3625900 [Available on 04/01/14]; PMCR: 2014/04/01 00:00; 2013/02/01 [aheadofprint]; ppublish