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. © 2004 Wiley‐Liss, Inc.