Mitochondrial calcium transport is regulated by P2Y1- and P2Y2-like mitochondrial receptors.
Ischemia-reperfusion injury remains a major clinical problem in liver transplantation. One contributing factor is mitochondrial calcium (mCa(2+)) overload, which triggers apoptosis; calcium also regulates mitochondrial respiration and adenosine 5'-triphosphate (ATP) production. Recently, we reported the presence of purinergic P2Y(1)- and P2Y(2)-like receptor proteins in mitochondrial membranes. Herein, we present an evaluation of the functional characteristics of these receptors. In experiments with isolated mitochondria, specific P2Y(1) and P2Y(2) receptors ligands: 2-methylthio-adenosine 5'-diphosphate (2meSADP) and uridine 5'-triphosphate (UTP), respectively, were used, and mitochondrial calcium uptake was measured. 2meSADP and UTP had a maximum effect at concentrations in the range of the known P2Y(1) and P2Y(2) receptors. The P2Y inhibitor phosphate-6-azophenyl-2',4'-disulfonate (PPADS) blocked the effects of both ligands. The phospholipase C (PLC) antagonist U73122 inhibited the effect of both ligands while its inactive analog U73343 had no effect. These data strongly support the hypothesis that mitochondrial Ca(2+) uptake is regulated in part by adenine nucleotides via a P2Y-like receptor mechanism that involves mitochondrial PLC activation.
Belous
Andrey E
AE
Department of Surgical Sciences, Vanderbilt University School of Medicine, 1161, 21st Avenue South, Medical Center North, Room CC2320, Nashville, Tennessee 37232-4753, USA.
Jones
Christopher M
CM
Wakata
Aya
A
Knox
Clayton D
CD
Nicoud
Ian B
IB
Pierce
Janene
J
Chari
Ravi S
RS
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D008024:Ligands; D024101:Mitochondrial Proteins; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D000266:Adenylyl Imidodiphosphate; D000244:Adenosine Diphosphate; D010738:Type C Phospholipases; D002118:Calcium