Volume 10 Supplement 2

Proceedings of the 2012 Sino-American Symposium on Clinical and Translational Medicine (SAS-CTM)

Open Access

The effects of mitochondrial Ca2+ transport on intracellular Ca2+ waves in cardiomyocytes

  • Zhenghang Zhao1, 2Email author,
  • Dandan Xiao1,
  • Nadezhda Fefelova2 and
  • Lai-Hua Xie2
Journal of Translational Medicine201210(Suppl 2):A67

https://doi.org/10.1186/1479-5876-10-S2-A67

Published: 17 October 2012

Background

Recent studies have implicated that mitochondria play important roles in intracellular Ca2+ homeostasis of cardiac myocytes. The major pathways for mitochondrial Ca2+ transport include mitochondrial Ca2+ uniporter and Na+/Ca2+ exchanger, as well as mitochondrial permeability transition pore (mPTP) under certain pathophysiological conditions. However, it is still unclear if mitochondrial Ca2+ flux can affect the generation of Ca2+ waves and triggered activities in cardiomyocytes.

Methods and results

Cytosolic Ca2+ (Cai2+) was imaged in fluo-4-AM loaded ventricular myocytes isolated from mice. Spontaneous SR Ca2+ release and Ca2+ waves (CaWs) were induced in the presence of high external Ca2+ (Cao2+, 4 mM). The protonophore carbonyl cyanide p - (trifluoromethoxy) phenylhydrazone (FCCP) reversibly raised basal Cai2+ levels in the presence, as well as absence of Cao2+, suggesting Ca2+ release from intracellular stores. Mitochondrial membrane potential (ΔΨm) was monitored by TMRM fluorescence. FCCP at 0.01- 0.1 µM, which partially depolarized ΔΨm, increased the frequency and amplitude of CaWs in a dose-dependent manner. Simultaneous recording of cell membrane potentials showed the augmentation of delayed after depolarization amplitudes and frequencies, and induction of triggered action potentials. On the contrary, FCCP at higher concentrations (>0.5 µM), which completely dissipated ΔΨm, eliminated CaWs while the basal Cai2+ remained high. The cease of CaWs was most likely due to the reduction of SR Ca2+ content as evaluated by rapid exposure to10 mM caffeine. Blocking sarcolemmal Na+-Ca2+ exchanger by substituting Na+ with Li+ in the perfusant further elevated basal Cai2+ and restored CaWs. The effect of FCCP on CaWs was mimicked by antimycin A (an electron transport chain inhibitor disrupting ΔΨm) or Ru360 (a mitochondrial Ca2+ uniporter inhibitor), but not by oligomycin (an ATP synthase inhibitor) or iodoacetic acid (a glycolytic inhibitor), excluding the contribution of intracellular ATP levels. The effects of FCCP on CaWs were counteracted by the mitochondrial permeability transition pore blocker cyclosporine A, or the mitochondrial Ca2+ uniporter activator kaempferol.

Conclusions

Mitochondrial Ca2+ release and uptake control plasma Ca2+ levels and plays an important role in regulation of intracellular CaWs and arrhythmogenesis.

Authors’ Affiliations

(1)
Department of Pharmacology, Medical School, Xi’an Jiaotong University
(2)
Department of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School

Copyright

© Zhao et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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