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The Journal of Neuroscience, November 1, 1999, 19(21):9261-9270

Mitochondria Regulate the Ca²⁺-Exocytosis Relationship of Bovine Adrenal Chromaffin Cells

David R. Giovannucci¹, Michael D. Hlubek², and Edward L. Stuenkel¹

Departments of ¹ Physiology and ² Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622

The present study expands the contemporary view of mitochondria as important participants in cellular Ca²⁺ dynamics and provides evidence that mitochondria regulate the supply of release-competent secretory granules. Using pharmacological probes to inhibit mitochondrial Ca²⁺ import, the ability of mitochondria to modulate secretory activity in single, patch-clamped bovine chromaffin cells was examined by simultaneously monitoring rapid changes in membrane surface area (C_m) and cytosolic Ca²⁺ levels ([Ca²⁺]_c). Repetitive step depolarizations or action potential waveforms were found to raise the [Ca²⁺]_c of chromaffin cells into the 1 µM to tens of micromolar range. Inhibiting mitochondria by treatment with carbonyl cyanide p-(trifuoro-methoxy)phenylhydrazone, antimycin-oligomycin, or ruthenium red revealed that mitochondria are a prominent component for the clearance of Ca²⁺ that entered via voltage-activated Ca²⁺ channels. Disruption of cellular Ca²⁺ homeostasis by poisoning mitochondria enhanced the secretory responsiveness of chromaffin cells by increasing the amplitude of the transient rise and the time course of recovery to baseline of the evoked [Ca²⁺]_c. The enhancement of the secretory response was represented by significant deviation of the Ca²⁺-exocytosis relationship from a standard relationship that equates Ca²⁺ influx and C_m. Thus, mitochondria would play a critical role in the control of secretory activity in chromaffin cells that undergo tonic or repetitive depolarizing activity, likely by limiting the Ca²⁺-dependent activation of specific proteins that recruit or prime secretory granules for exocytosis.

Key words: membrane capacitance; exocytosis; FCCP; fura-2; furaptra; readily releasable pool

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19219261-10$05.00/0

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