Mitochondrial Ca2+ uptake is inhibited by a concerted action of p38 MAPK and protein kinase D.
Angiotensin II elicits cytosolic Ca2+ signal that is transferred into the mitochondria. Previously we found in H295R cells that this signal transfer is enhanced by both the inhibition of p38 MAPK and a novel isoform of PKC [G. Szanda, P. Koncz, A. Rajki, A. Spät, Participation of p38 MAPK and a novel-type protein kinase C in the control of mitochondrial Ca2+ uptake, Cell Calcium 43 (2008) 250-259]. Now we report that simultaneous activation of these protein kinases (by TNFalpha and PMA+an inhibitor of the conventional PKC isoforms, respectively) attenuates the transfer of cytosolic Ca2+ signal, elicited by depolarisation or store-operated Ca2+ influx, into the mitochondria. The Ca2+ uptake enhancing effect of the p38 MAPK inhibitor SB202190 is due to the inhibition of p38 MAPK and not to a direct mitochondrial action. Protein kinases reduce mitochondrial [Ca2+] by inhibiting the uptake mechanism. The threshold of mitochondrial Ca2+ uptake may depend on the activity of p38 MAPK. The silencing of protein kinase D (PKD) also results in enhanced transfer of Ca2+ signal from the cytosol into the mitochondria. Our data indicate that Ca2+ mobilising agonists, through the simultaneous activation of p38 MAPK, a novel PKC isoform and PKD, exert a negative feed-forward action on mitochondrial Ca2+ uptake, thus reducing the risk of Ca2+ overload.
Koncz
Péter
P
Department of Physiology, Faculty of Medicine, Semmelweis University and Laboratory of Neurobiochemistry and Molecular Physiology, Hungarian Academy of Sciences, P.O. Box 259, H-1444 Budapest, Hungary.
Szanda
Gergo
G
Fülöp
László
L
Rajki
Anikó
A
Spät
András
A
D000804:Angiotensin II / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D025461:Feedback, Physiological; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C089212:protein kinase D; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D002118:Calcium