Mitochondrial regulation of sarcoplasmic reticulum Ca2+ content in vascular smooth muscle cells.
Subplasmalemmal ion fluxes have global effects on Ca(2+) signaling in vascular smooth muscle. Measuring cytoplasmic and mitochondrial [Ca(2+)]and [Na(+)], we previously showed that mitochondria buffer both subplasmalemmal cytosolic [Ca(2+)] and [Na(+)] in vascular smooth muscle cells. We have now directly measured sarcoplasmic reticulum [Ca(2+)] in aortic smooth muscle cells, revealing that mitochondrial Na(+)/Ca(2+) exchanger inhibition with CGP-37157 impairs sarcoplasmic reticulum Ca(2+) 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 [Ca(2+)] elevations, despite increased cytosolic [Ca(2+)] elevations. Reversal of plasmalemmal Na(+)/Ca(2+) exchange was the primary Ca(2+) 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(+)/Ca(2+) exchanger to funnel Ca(2+) into the sarcoplasmic reticulum and minimize cytosolic [Ca(2+)] elevations that might otherwise contribute to hypertensive or proliferative vasculopathies.
Poburko
Damon
D
Department of Cell Physiology and Metabolism, University of Geneva, 1 Michel-Servet, CH-1211 Geneva 4, Switzerland. Damon.Poburko@medecine.unige.ch
Liao
Chiu-Hsiang
CH
van Breemen
Cornelis
C
Demaurex
Nicolas
N
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D006973:Hypertension / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008931:Mitochondria, Muscle / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C476525:FIS1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D002998:Clonazepam; C079032:CGP 37157; D000255:Adenosine Triphosphate; D012964:Sodium; D013890:Thiourea; D002118:Calcium