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(Circulation Research. 2009;104:104.)
© 2009 American Heart Association, Inc.

Cellular Biology

Mitochondrial Regulation of Sarcoplasmic Reticulum Ca²⁺ Content in Vascular Smooth Muscle Cells

Damon Poburko^*, Chiu-Hsiang Liao^*, Cornelis van Breemen, Nicolas Demaurex

From the Department of Cell Physiology and Metabolism (D.P., C-H.L., N.D.), University of Geneva, Switzerland; and Department of Anesthesiology, Pharmacology & Therapeutics (C-H.L., C.v.B.), University of British Columbia, Vancouver, Canada.

Correspondence to Dr Damon Poburko, Department of Cell Physiology and Metabolism, University of Geneva, 1 Michel-Servet, CH-1211 Geneva 4, Switzerland. E-mail Damon.Poburko{at}medecine.unige.ch

Subplasmalemmal ion fluxes have global effects on Ca²⁺ signaling in vascular smooth muscle. Measuring cytoplasmic and mitochondrial [Ca²⁺]and [Na⁺], we previously showed that mitochondria buffer both subplasmalemmal cytosolic [Ca²⁺] and [Na⁺] in vascular smooth muscle cells. We have now directly measured sarcoplasmic reticulum [Ca²⁺] in aortic smooth muscle cells, revealing that mitochondrial Na⁺/Ca²⁺ exchanger inhibition with CGP-37157 impairs sarcoplasmic reticulum Ca²⁺ refilling during purinergic stimulation. By overexpressing hFis1 to remove mitochondria from the subplasmalemmal space, we show that the rate and extent of sarcoplasmic reticulum refilling is augmented by a subpopulation of peripheral mitochondria. In ATP-stimulated cells, hFis-1–mediated relocalization of mitochondria impaired the sarcoplasmic reticulum refilling process and reduced mitochondrial [Ca²⁺] elevations, despite increased cytosolic [Ca²⁺] elevations. Reversal of plasmalemmal Na⁺/Ca²⁺ exchange was the primary Ca²⁺ entry mechanism following ATP stimulation, based on the effects of KB-R7943. We propose that subplasmalemmal mitochondria ensure efficient sarcoplasmic reticulum refilling by cooperating with the plasmalemmal Na⁺/Ca²⁺ exchanger to funnel Ca²⁺ into the sarcoplasmic reticulum and minimize cytosolic [Ca²⁺] elevations that might otherwise contribute to hypertensive or proliferative vasculopathies.

Key Words: hFis1 • mitochondria • fragmentation • D1ER • sarcoplasmic reticulum