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

• Published in: American journal of physiology. Heart and circulatory physiology 2013-04, Vol.304 (7), p.H983-H993
• Main Authors: Zima, Aleksey V, Pabbidi, Malikarjuna R, Lipsius, Stephen L, Blatter, Lothar A
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Adenosine Triphosphate - metabolism; Animals; Calcium - metabolism; Calcium Signaling - drug effects; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - pharmacology; Cats; Cytosol - metabolism; Excitation Contraction Coupling - drug effects; Glycolysis; Heart Atria - cytology; Magnesium - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Oligomycins - pharmacology; Oxidative Phosphorylation; Proton Ionophores - pharmacology; Proton-Translocating ATPases - metabolism; Sarcoplasmic Reticulum - metabolism; Sodium - metabolism; Uncoupling Agents - pharmacology
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00932.2012

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 (ΔΨm) 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. ΔΨm 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. ΔΨm 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.