Role of perinuclear mitochondria in the spatiotemporal dynamics of spontaneous Ca2+ waves in interstitial cells of Cajal-like cells of the rabbit urethra.

Hikaru Hashitani, Hikaru Hashiatni, Richard J Lang, Hikaru Suzuki

Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. hasitani@med.nagoya-cu.ac.jp

British journal of pharmacology 2010 Oct

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Although spontaneous Ca(2+) waves in interstitial cells of Cajal (ICC)-like cells (ICC-LCs) primarily arise from endoplasmic reticulum (ER) Ca(2+) release, the interactions among mitochondrial Ca(2+) buffering, cellular energetics and ER Ca(2+) release in determining the spatiotemporal dynamics of intracellular Ca(2+) remain to be elucidated. Spontaneous Ca(2+) transients in freshly isolated ICC-LCs of the rabbit urethra were visualized using fluo-4 Ca(2+) imaging, while the intracellular distribution of mitochondria was viewed with MitoTracker Red. Spontaneous Ca(2+) waves invariably originated from the perinuclear region where clusters of mitochondria surround the nucleus. Perinuclear Ca(2+) dynamics were characterized by a gradual rise in basal Ca(2+) that preceded each regenerative Ca(2+) transient. Caffeine evoked oscillatory Ca(2+) waves originating from anywhere within ICC-LCs. Ryanodine or cyclopiazonic acid prevented Ca(2+) wave generation with a rise in basal Ca(2+), and subsequent caffeine evoked a single rudimentary Ca(2+) transient. Inhibition of glycolysis with 2-deoxy-glucose or carbonyl cyanide 3-chlorophenylhydrazone, a mitochondrial protonophore, increased basal Ca(2+) and abolished Ca(2+) waves. However, caffeine still induced oscillatory Ca(2+) transients. Mitochondrial Ca(2+) uptake inhibition with RU360 attenuated Ca(2+) wave amplitudes, while mitochondrial Ca(2+) efflux inhibition with CGP37157 suppressed the initial Ca(2+) rise to reduce Ca(2+) wave frequency. Perinuclear mitochondria in ICC-LCs play a dominant role in the spatial regulation of Ca(2+) wave generation and may regulate ER Ca(2+) release frequency by buffering Ca(2+) within microdomains between both organelles. Glycolysis inhibition reduced mitochondrial Ca(2+) buffering without critically disrupting ER function. Perinuclear mitochondria may function as sensors of intracellular metabolites.

Citation

Hikaru Hashitani, Hikaru Hashiatni, Richard J Lang, Hikaru Suzuki. Role of perinuclear mitochondria in the spatiotemporal dynamics of spontaneous Ca2+ waves in interstitial cells of Cajal-like cells of the rabbit urethra. British journal of pharmacology. 2010 Oct;161(3):680-94