Diacylglycerols activate mitochondrial cationic channel(s) and release sequestered Ca(2+).
Mitochondria contribute to cytosolic Ca(2+) homeostasis through several uptake and release pathways. Here we report that 1,2-sn-diacylglycerols (DAG's) induce Ca(2+) release from Ca(2+)-loaded mammalian mitochondria. Release is not mediated by the uni-porter or the Na(+)/Ca(2+) exchanger, nor is it attributed to putative catabolites. DAG's-induced Ca(2+) efflux is biphasic. Initial release is rapid and transient, insensitive to permeability transition inhibitors, and not accompanied by mitochondrial swelling. Following initial rapid release of Ca(2+) and relatively slow reuptake, a secondary progressive release of Ca(2+) occurs, associated with swelling, and mitigated by permeability transition inhibitors. The initial peak of DAG's-induced Ca(2+) efflux is abolished by La(3+) (1 mM) and potentiated by protein kinase C inhibitors. Phorbol esters, 1,3-diacylglycerols and 1-monoacylglycerols do not induce mitochondrial Ca(2+) efflux. Ca(2+)-loaded mitoplasts devoid of outer mitochondrial membrane also exhibit DAG's-induced Ca(2+) release, indicating that this mechanism resides at the inner mitochondrial membrane. Patch clamping brain mitoplasts reveal DAG's-induced slightly cation-selective channel activity that is insensitive to bongkrekic acid and abolished by La(3+). The presence of a second messenger-sensitive Ca(2+) release mechanism in mitochondria could have an important impact on intracellular Ca(2+) homeostasis.
Chinopoulos
Christos
C
Department of Anesthesiology, University of Maryland, Baltimore, Maryland 21201, USA.
Starkov
Anatoly A
AA
Grigoriev
Sergey
S
Dejean
Laurent M
LM
Kinnally
Kathleen W
KW
Liu
Xibao
X
Ambudkar
Indu S
IS
Fiskum
Gary
G
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology*; D004789:Enzyme Activation; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D027723:Ipomoea batatas / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004075:Diglycerides; D007473:Ion Channels; D019831:Sodium-Calcium Exchanger; C034703:mitochondrial calcium uniporter; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D002118:Calcium