title: Control mechanisms of mitochondrial Ca(2+) uptake - feed-forward modulation of aldosterone secretion.
abstract: Mitochondrial Ca(2+) signal activates metabolism by boosting pyridine nucleotide reduction and ATP synthesis or, if Ca(2+) sequestration is supraphysiological, may even lead to apoptosis. Although the molecular background of mitochondrial Ca(2+) uptake has recently been elucidated, the regulation of Ca(2+) handling is still not properly clarified. In human adrenocortical H295R cells we found a regulatory mechanism involving p38 MAPK and novel-type PKC isoforms. Upon stimulation with angiotensin II (AII) these kinases are activated typically prior to the release of Ca(2+) and - most probably by reducing the Ca(2+) permeation through the outer mitochondrial membrane - attenuate mitochondrial Ca(2+) uptake in a feed-forward manner. The biologic significance of the kinase-mediated reduction of mitochondrial Ca(2+) signal is also reflected by the attenuation of AII-mediated aldosterone secretion. As another feed-forward mechanism, we found in HEK-293T and H295R cells that Ca(2+) signal evoked either by IP(3) or by voltage-gated influx is accompanied by a concomitant cytosolic Mg(2+) signal. In permeabilized HEK-293T cells Mg(2+) was found to be a potent inhibitor of mitochondrial Ca(2+) uptake in the physiologic [Mg(2+)] and [Ca(2+)] range. Thus, these inhibitory mechanisms may serve not only as protection against mitochondrial Ca(2+) overload and subsequent apoptosis but also have the potential to substantially alter physiological responses.
authors.affiliation: Department of Physiology, Semmelweis University, POB 259, H-1444 Budapest, Hungary.
authors.forename: Gergö
authors.initials: G
authors.lastname: Szanda
authors.forename: Anikó
authors.initials: A
authors.lastname: Rajki
authors.forename: András
authors.initials: A
authors.lastname: Spät
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007295:Inositol Phosphates; D007527:Isoenzymes; D000450:Aldosterone; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D008274:Magnesium; D002118:Calcium