Spontaneous mitochondrial depolarizations are independent of SR Ca2+ release

O'Reilly, C.M. and Fogarty, K.E. and Drummond, R.M. and Tuft, R.A. and Walsh, J.V. (2004) Spontaneous mitochondrial depolarizations are independent of SR Ca2+ release. American Journal of Physiology - Cell Physiology, 286 (5). C1139-51. ISSN 0363-6143 (https://doi.org/10.1152/ajpcell.00371.2003)

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Abstract

The mitochondrial membrane potential (ΔΨm) underlies many mitochondrial functions, including Ca2+ influx into the mitochondria, which allows them to serve as buffers of intracellular Ca2+. Spontaneous depolarizations of ΔΨm, flickers, have been observed in isolated mitochondria and intact cells using the fluorescent cationic lipophile tetramethylrhodamine ethyl ester (TMRE), which distributes across the inner mitochondrial membrane in accordance with the Nernst equation. Flickers in cardiomyocytes have been attributed to uptake of Ca2+ released from the sarcoplasmic reticulum (SR) via ryanodine receptors in focal transients called Ca2+ sparks. We have shown previously that an increase in global Ca2+ in smooth muscle cells causes an increase in mitochondrial Ca2+ and depolarization of ΔΨm. Here we sought to determine whether flickers in smooth muscle cells are caused by uptake of Ca2+ released focally in Ca2+ sparks. High-speed three-dimensional imaging was used to monitor ΔΨm in freshly dissociated myocytes from toad stomach that were simultaneously voltage clamped at 0 mV to ensure the cytosolic TMRE concentration was constant and equal to the low level in the bath (2.5 nM). This approach allows quantitative analysis of flickers as we have previously demonstrated. Depletion of SR Ca2+ not only failed to eliminate flickers but rather increased their magnitude and frequency somewhat. Flickers were not altered in magnitude or frequency by ryanodine or xestospongin C, inhibitors of intracellular Ca2+ release, or by cyclosporin A, an inhibitor of the permeability transition pore. Focal Ca2+ release from the SR does not cause flickers in the cells employed here.

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