Inhibition of Phospholipase C Attenuates Liver Mitochondrial Calcium Overload Following Cold Ischemia

Knox, Clayton D.; Pierce, Janene; Nicoud, Ian B.; Belous, Andrey E.; Jones, Christopher M.; Anderson, Christopher; Chari, Ravi S.

doi:10.1097/01.tp.0000199267.98971.77

Cited by 9 publications

(9 citation statements)

References 31 publications

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“…The duration of liver ischemia correlates to the frequency and severity of postreperfusion hepatic dysfunction (10,13,25,46), which may result in subsequent liver failure (36). The pathogenesis of I/R injury is multifactorial (9,26,34,52,53), but altered cellular and mitochondrial Ca 2ϩ handling are known to be of central importance, and many investigators agree that control of mitochondrial and cellular Ca 2ϩ homeostasis represents an important strategy for preventing I/R damage (28,32,56,59).…”

Section: Discussionmentioning

confidence: 97%

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2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake

Nicoud

Knox²,

Jones³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ischemia-reperfusion (I/R) injury is a commonly encountered clinical problem in liver surgery and transplantation. The pathogenesis of I/R injury is multifactorial, but mitochondrial Ca(2+) overload plays a central role. We have previously defined a novel pathway for mitochondrial Ca(2+) handling and now further characterize this pathway and investigate a novel Ca(2+)-channel inhibitor, 2-aminoethoxydiphenyl borate (2-APB), for preventing hepatic I/R injury. The effect of 2-APB on cellular and mitochondrial Ca(2+) uptake was evaluated in vitro by using (45)Ca(2+). Subsequently, 2-APB (2 mg/kg) or vehicle was injected into the portal vein of anesthetized rats either before or following 1 h of inflow occlusion to 70% of the liver. After 3 h of reperfusion, liver injury was assessed enzymatically and histologically. Hep G2 cells transfected with green fluorescent protein-tagged cytochrome c were used to evaluate mitochondrial permeability. 2-APB dose-dependently blocked Ca(2+) uptake in isolated liver mitochondria and reduced cellular Ca(2+) accumulation in Hep G2 cells. In vivo I/R increased liver enzymes 10-fold, and 2-APB prevented this when administered pre- or postischemia. 2-APB significantly reduced cellular damage determined by hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of liver tissue. In vitro I/R caused a dissociation between cytochrome c and mitochondria in Hep G2 cells that was prevented by administration of 2-APB. These data further establish the role of cellular Ca(2+) uptake and subsequent mitochondrial Ca(2+) overload in I/R injury and identify 2-APB as a novel pharmacological inhibitor of liver I/R injury even when administered following a prolonged ischemic insult.

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Section: Discussionmentioning

confidence: 97%

“…Not surprisingly, selective inhibition of phospholipase C prevents mCa 2ϩ uptake and minimizes I/R damage in the liver (4,31,32). During these previous studies, we discovered another novel cell-permeable inhibitor of mCa 2ϩ uptake, 2-aminoethoxydiphenyl borate (2-APB).…”

mentioning

confidence: 95%

2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake

Nicoud

Knox²,

Jones³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…During the cold ischemia time ATP is degraded to hypoxanthine. The catabolism of adenine nucleotides results in an accumulation of hypoxanthine in ischemic cells [12]. Ischemia is also associated with the proteolytic conversion of xanthine dehydrogenase to xanthine oxidase.…”

Section: Discussionmentioning

confidence: 99%

Post-hypoxic cellular disintegration in glycine-preserved renal tubules is attenuated by hydroxyl radical scavengers and iron chelators

Moussavian

Slotta

Kollmar

et al. 2008

Langenbecks Arch Surg

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“…PLC-δ1 has been reported to localize to mitochondria and to facilitate mitochondrial calcium uptake [76, 77] through the mitochondrial calcium uniporter. PI4,5P 2 hydrolysis generates both phosphatidylinositol 3,4,5-triphsophate (IP 3 ) and DAG; the latter in this case is thought to be the relevant lipid signal that stimulates the Ca 2+ uptake [54].…”

Section: Pa Signaling Pathways On the Mitochondrial Surfacementioning

confidence: 99%

Lipid signaling on the mitochondrial surface

Huang

Frohman

2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Summary Regulated production and elimination of the signaling lipids phosphatidic acid (PA), diacylglycerol (DAG), and phosphatidylinositol 4,5-bisphosphate (PI4,5P2) creates a complex and interconnected signaling network that modulates a wide variety of eukaryotic cell biological events. PA production at the plasma membrane and on trafficking membrane organelles by classical Phospholipase D (PLD) through the hydrolysis of phosphatidylcholine (PC) has been studied widely. In this chapter, we review a newly identified, non-canonical member of the PLD superfamily, MitoPLD, which localizes to the mitochondrial surface and plays a role in mitochondrial fusion via the hydrolysis of cardiolipin (CL) to generate PA. The role of PA in facilitating the mitochondrial fusion event carried out by proteins known as Mitofusins is intriguing in light of the role classic PLD-generated PA plays in facilitating SNARE-mediated fusion of secretory membrane vesicles into the plasma membrane. In addition, however, PA on the mitochondrial surface may also trigger a signaling cascade that elevates DAG, leading to downstream events that affect mitochondrial fission and energy production. PA production on the mitochondrial surface may also stimulate local production of PI4,5P2 to facilitate mitochondrial fission and subcellular trafficking or facilitate Ca2+ influx.

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Inhibition of Phospholipase C Attenuates Liver Mitochondrial Calcium Overload Following Cold Ischemia

Abstract: These data demonstrate that PLC-dl is essential for mCa uptake following CI, and that the PLC pathway may be sensitized by CI. The CI-induced increase in mitochondrial PLC-delta1 expression represents a novel mechanism whereby mCa uptake can increase independently of cytosolic conditions.

Cited by 9 publications

References 31 publications

2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake

2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake

Post-hypoxic cellular disintegration in glycine-preserved renal tubules is attenuated by hydroxyl radical scavengers and iron chelators

Lipid signaling on the mitochondrial surface

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