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Mitochondrial calcium transport is regulated by P2Y1- and P2Y2-like mitochondrial receptors

Authors

  • Andrey E. Belous,

    1. Department of Surgical Sciences, Vanderbilt University School of Medicine, 1161, 21st Avenue South, Medical Center North, Room CC2320, Nashville, Tennessee 37232-4753
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  • Christopher M. Jones,

    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
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  • Aya Wakata,

    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
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  • Clayton D. Knox,

    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
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  • Ian B. Nicoud,

    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
    2. Department of Cancer Biology, Vanderbilt University School of Medicine, 23rd and Pierce Avenues, 771 Preston Building, Nashville, Tennessee 37232-6840
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  • Janene Pierce,

    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
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  • Ravi S. Chari

    Corresponding author
    1. Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Suite 801 Oxford House, 1313, 21st Avenue South, Nashville, Tennessee 37232-4753
    2. Department of Cancer Biology, Vanderbilt University School of Medicine, 23rd and Pierce Avenues, 771 Preston Building, Nashville, Tennessee 37232-6840
    • Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Suite 801 Oxford House, 1313, 21st Avenue South, Vanderbilt University Medical Center, Nashville, TN 37232-4753.
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Abstract

Ischemia-reperfusion injury remains a major clinical problem in liver transplantation. One contributing factor is mitochondrial calcium (mCa2+) overload, which triggers apoptosis; calcium also regulates mitochondrial respiration and adenosine 5′-triphosphate (ATP) production. Recently, we reported the presence of purinergic P2Y1- and P2Y2-like receptor proteins in mitochondrial membranes. Herein, we present an evaluation of the functional characteristics of these receptors. In experiments with isolated mitochondria, specific P2Y1 and P2Y2 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 P2Y1 and P2Y2 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 Ca2+ uptake is regulated in part by adenine nucleotides via a P2Y-like receptor mechanism that involves mitochondrial PLC activation. J. Cell. Biochem. 99: 1165–1174, 2006. © 2006 Wiley-Liss, Inc.

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