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Agonist-induced mitochondrial Ca²⁺ transients in smooth muscle

TANIA SZADO^*, KUO-HSING KUO^*, KATY BERNARD-HELARY, DAMON POBURKO^*, CHENG HAN LEE^*, CHUN SEOW^*, URS T. RUEGG^,1 and CORNELIS VAN BREEMEN^*,12

^* The iCAPTUR⁴E Center, University of British Columbia, St. Paul’s Hospital, Vancouver, BC, and Cardiovascular Sciences, Children’s and Women’s Health Centre of British Columbia, Vancouver, BC, Canada; and
Pharmacology Group, School of Pharmacy, University of Lausanne, 1015 Lausanne, Switzerland

²Correspondence: Cardiovascular Research, BC Research Institute for Children’s and Women’s Health, 2082–950 W. 28th Ave., Vancouver BC, Canada V5Z 4H4. E-mail: breemen{at}interchange.ubc.ca

We investigated the role of mitochondria (MT) in calcium signaling in a culture of rat aortic smooth muscle cells. We used targeted aequorin to selectively measure [Ca²⁺] in this organelle. Our results reveal that smooth muscle cell stimulation with agonists causes a large, transient increase in mitochondrial [Ca²⁺] ([Ca²⁺]_m). This large transient can be blocked with inhibitors of the sarco-endoplasmic reticulum Ca²⁺-ATPase, suggesting a close relationship between the sarcoplasmic reticulum (SR) and the mitochondria. FCCP completely abolished the response to agonists, and targeted mitochondrial GFP revealed a vast tubular network of MT in these cells. When added before stimulation with ATP, IP₃ inhibitors partially blocked the ATP-induced rise in mitochondrial Ca²⁺ release. The role of the Na⁺/Ca²⁺ exchanger (NCX) was examined by removing extracellular Na⁺. This procedure prevented the decrease in the [Ca²⁺]_m transient normally seen on removal of extracellular Ca²⁺. We propose a functional linkage of MT and SR dependent on a narrow junctional space between the two organelles in which Ca²⁺ diffusion is restricted. Approximately half of the mitochondria appear to be associated with the superficial SR, which communicates with the extracellular space via NCX.—Szado, T., Kuo, K.-H., Bernard-Helary, K., Poburko, D., Lee, C. H., Seow, C., Ruegg, U. T., van Breemen, C. Agonist-induced mitochondrial Ca²⁺ transients in smooth muscle.

Key Words: calcium • mitochondria • sarcoplasmic reticulum • SMC

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