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© The Rockefeller University Press, 0021-9525/1999//795 $5.00
The Journal of Cell Biology, Volume 145, Number 4, , 1999 795-808

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Mitochondria Exert a Negative Feedback on the Propagation of Intracellular Ca2+ Waves in Rat Cortical Astrocytes



Eric Boitier, Ruth Rea, and Michael R. Duchen

Department of Physiology, University College London, London, WC1E 6BT, United Kingdom

We have used digital fluorescence imaging techniques to explore the interplay between mitochondrial Ca2+ uptake and physiological Ca2+ signaling in rat cortical astrocytes. A rise in cytosolic Ca2+ ([Ca2+]cyt), resulting from mobilization of ER Ca2+ stores was followed by a rise in mitochondrial Ca2+ ([Ca2+]m, monitored using rhod-2). Whereas [Ca2+]cyt recovered within ~1 min, the time to recovery for [Ca2+]m was ~30 min. Dissipating the mitochondrial membrane potential ({Delta}{psi}m, using the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenyl-hydrazone [FCCP] with oligomycin) prevented mitochondrial Ca2+ uptake and slowed the rate of decay of [Ca2+]cyt transients, suggesting that mitochondrial Ca2+ uptake plays a significant role in the clearance of physiological [Ca2+]cyt loads in astrocytes. Ca2+ signals in these cells initiated either by receptor-mediated ER Ca2+ release or mechanical stimulation often consisted of propagating waves (measured using fluo-3). In response to either stimulus, the wave traveled at a mean speed of 22.9 ± 11.2 µm/s (n = 262). This was followed by a wave of mitochondrial depolarization (measured using tetramethylrhodamine ethyl ester [TMRE]), consistent with Ca2+ uptake into mitochondria as the Ca2+ wave traveled across the cell. Collapse of {Delta}{psi}m to prevent mitochondrial Ca2+ uptake significantly increased the rate of propagation of the Ca2+ waves by 50%. Taken together, these data suggest that cytosolic Ca2+ buffering by mitochondria provides a potent mechanism to regulate the localized spread of astrocytic Ca2+ signals.

Key Words: intracellular Ca2+ waves • astrocytes • mitochondria • negative feedback • Ca2+ buffering

Abbreviations used in this paper: [Ca2+]cyt, cytosolic Ca2+; [Ca2+]m, mitochondrial Ca2+; [Ca2+]n, nuclear Ca2+; CNS, central nervous system; FCCP, carbonyl cyanide p-trifluoromethoxy-phenyl-hydrazone; IP3, inositol 1,4,5-trisphosphate; {Delta}{psi}m, mitochondrial membrane potential; SD, Leao's spreading depression; TMRE, tetramethylrhodamine ethyl ester.

Some animated sequences of images that have been used to provide data for this paper can be viewed on the web at http://www.geribolsover. physiol.ucl.ac.uk/Boitier/wave.html


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