When is high-Ca+ microdomain required for mitochondrial Ca+ uptake?
Ca(2+) release from IP(3)-sensitive stores in the endoplasmic reticulum (ER) induced by Ca(2+)-mobilizing agonists generates high-Ca(2+) microdomains between ER vesicles and neighbouring mitochondria. Here we present a model that describes when such microdomains are required and when submicromolar [Ca(2+)] is sufficient for mitochondrial Ca(2+) uptake. Mitochondrial Ca(2+) uptake rate in angiotensin II-stimulated H295R adrenocortical cells correlates with the proximity between ER vesicles and the mitochondrion, reflecting the uptake promoting effect of high-Ca(2+) peri-mitochondrial microdomains. Silencing or inhibition of p38 mitogen-activated protein kinase (MAPK) or inhibition of the novel isoforms of protein kinase C enhances mitochondrial Ca(2+) uptake and abolishes the positive correlation between Ca(2+) uptake and ER-mitochondrion proximity. Inhibition of protein phosphatases attenuates mitochondrial Ca(2+) uptake and also abolishes its positive correlation with ER-mitochondrion proximity. We postulate that during IP(3)-induced Ca(2+) release, Ca(2+) uptake is confined to ER-close mitochondria, because of the simultaneous activation of the protein kinases. Attenuation of Ca(2+) uptake prevents Ca(2+) overload of mitochondria and thus protects the cell against apoptosis. On the other hand, all the mitochondria accumulate Ca(2+) at a non-inhibited rate during physiological Ca(2+) influx through the plasma membrane. Membrane potential is higher in ER-distant mitochondria, providing a bigger driving force for Ca(2+) uptake. Our model explains why comparable mitochondrial Ca(2+) signals are formed in response to K(+) and angiotensin II (equipotent in respect to global cytosolic Ca(2+) signals), although only the latter generates high-Ca(2+) microdomains.
Spät
A
A
Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary. spat@puskin.sote.hu
Fülöp
L
L
Koncz
P
P
Szanda
G
G
D000804:Angiotensin II / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism
D002352:Carrier Proteins; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium