Mitochondrial P2Y-Like receptors link cytosolic adenosine nucleotides to mitochondrial calcium uptake.
ATP is a known extracellular ligand for cell membrane purinergic receptors. Intracellular ATP can work also as a regulatory ligand via binding sites on functional proteins. We report herein the existence of P2Y(1)-like and P2Y(2)-like receptors in hepatocyte mitochondria (mP2Y(1) and mP2Y(2)), which regulate mCa(2+) uptake though the uniporter. Mitochondrial P2Y(1) activation stimulates mCa(2+) uptake; whereas, mP2Y(2) activation inhibits mCa(2+) uptake. ATP acts preferentially on mP2Y(2) receptors, while ADP and AMP-PNP stimulate both the mP2Y(1) and mP2Y(2). PPADS inhibits ADP stimulated mP2Y(1)-mediated mCa(2+) uptake. In addition, UTP, a selective P2Y(2) agonist, strongly inhibits mCa(2+) uptake. The newly discovered presence and function of these receptors is significant because it explains increased mCa(2+) uptake in the setting of low cytosolic [ATP] and, therefore, establishes a mechanism for direct feedback in which cytosolic [ATP] governs mitochondrial ATP production through regulation of mCa(2+) uptake.
Belous
Andrey
A
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753, USA.
Wakata
Aya
A
Knox
Clayton D
CD
Nicoud
Ian B
IB
Pierce
Janene
J
Anderson
Christopher D
CD
Pinson
C Wright
CW
Chari
Ravi S
RS
D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2
D000227:Adenine Nucleotides; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2