Relation between accumulation of phospholipase A2 reaction products and Ca2+ release in isolated liver mitochondria

Rustenbeck, Ingo; Münster, Wilfried; Lenzen, Sigurd

doi:10.1016/s0005-2760(96)00113-0

Cited by 21 publications

(19 citation statements)

References 46 publications

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“…19 Furthermore, it is known that LC plays a protective role against various mitochondrial toxins in animal model and tissues. 45,46 In agreement with these findings, we showed that LC suppressed 3NP-induced Ca 2þ release from mitochondria, swelling, and cytochrome c release. These results suggest that 3NP increases free fatty acids in mitochondria through the activation of Ca 2þ -dependent PLA 2 , and thus LC suppresses mitochondrial MPT by consuming the fatty acids through b-oxidation which requires ATP or an ATP generation system.…”

supporting

confidence: 88%

“…Mitochondria (Mt, 0.5 mg protein mL À1 ) were incubated in standard incubation medium containing 0.5 mM Pi, 2.5 mM succinate, 250 mM ATP, 50 mM antipyrylazo III (Azo), and in the presence of 10 mM 3NP or 1 mM LC at 258C. Reaction was started by addition of 50 mM Ca However, Rustenbeck et al 46 reported that accumulated Ca 2þ m was released spontaneously by MPT without the production of free fatty acids and that mitochondria significantly increased the products of PLA 2 after continuous incubation in a PLA 2 -inhibitable mechanism. In addition, recent studies report that a neuroprotective action of LC was observed without the attenuation of succinate dehydrogenase inhibition in vivo 20 and that LC plays an important modulatory role in combination with ALC in signal transduction and gene expression pathways in neuronal cells.…”

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confidence: 99%

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Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

Nishimura¹,

Okimura²,

Fujita³

et al. 2008

Cell Biochemistry & Function

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3-Nitropropionic acid (3NP) functions as an irreversible inhibitor of succinic acid dehydrogenase (complex II) and induces neuronal disorders in rats similar to those in patients with Huntington's disease. It is well known that L-carnitine (LC), a carrier of long chain fatty acid into the mitochondrial matrix, attenuates the neuronal degeneration in 3NP-treated rats. From these findings it has been suggested that 3NP induces certain neuronal cell death through mitochondrial dysfunction and that LC preserves the neurons against the dysfunction of mitochondria caused by 3NP. However, the detailed mechanism of cell death by 3NP and the protective actions of LC against the mitochondrial dysfunction have not been fully elucidated yet. Thus, we studied the molecular mechanism of the effects of 3NP and LC on isolated rat liver mitochondria. 3NP inhibited succinate respiration and the decreased respiratory control ratio of isolated mitochondria without affecting oxidative phosphorylation. 3NP induced a membrane permeability transition (MPT), which plays an important role in the mechanism of apoptotic cell death. 3NP stimulated Ca 2þ release from mitochondria, decreased membrane potential, induced mitochondrial swelling, and stimulated cytochrome c release from mitochondria. 3NP-induced swelling was suppressed by bovine serum albumin, inhibitors of phospholipase A 2 and by an inhibitor of classic MPT, cyclosporin A. Furthermore, LC suppressed the changes brought about by 3NP in mitochondrial functions in the presence of ATP. These results suggest that MPT underlies the mechanism of 3NP-induced cell death, and that LC attenuates mitochondrial MPT by decreasing long chain fatty acids generated by phospholipase A 2 .

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confidence: 88%

mentioning

confidence: 99%

Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

Nishimura¹,

Okimura²,

Fujita³

et al. 2008

Cell Biochemistry & Function

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“…the lipid mediator platelet-activating factor and the experimental anticancer drug hexadecylphosphocholine), also influence mitochondrial Ca 2ϩ transport and membrane potential. Thus, an impairment of mitochondrial functions caused by the accumulation of PLA 2 products is very likely (85,86).…”

Section: Discussionmentioning

confidence: 99%

Rat Brain Cortex Mitochondria Release Group II Secretory Phospholipase A2 under Reduced Membrane Potential

Macchioni¹,

Corazzi²,

Nardicchi³

et al. 2004

Journal of Biological Chemistry

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Activation of brain mitochondrial phospholipase(s) A 2 (PLA 2 ) might contribute to cell damage and be involved in neurodegeneration. Despite the potential importance of the phenomenon, the number, identities, and properties of these enzymes are still unknown. Here, we demonstrate that isolated mitochondria from rat brain cortex, incubated in the absence of respiratory substrates, release a Ca 2؉ -dependent PLA 2 having biochemical properties characteristic to secreted PLA 2 (sPLA 2 ) and immunoreacting with the antibody raised against recombinant type IIA sPLA 2 (sPLA 2 -IIA). Under identical conditions, no release of fumarase in the extramitochondrial medium was observed. The release of sPLA 2 from mitochondria decreases when mitochondria are incubated in the presence of respiratory substrates such as ADP, malate, and pyruvate, which causes an increase of transmembrane potential determined by cytofluorimetric analysis using DiOC 6 (3) as a probe. The treatment of mitochondria with the uncoupler carbonyl cyanide 3-chlorophenylhydrazone slightly enhances sPLA 2 release. The increase of sPLA 2 specific activity after removal of mitochondrial outer membrane indicates that the enzyme is associated with mitoplasts. The mitochondrial localization of the enzyme has been confirmed by electron microscopy in U-251 astrocytoma cells and by confocal laser microscopy in the same cells and in PC-12 cells, where the structurally similar isoform type V-sPLA 2 has mainly nuclear localization. In addition to sPLA 2 , mitochondria contain another phospholipase A 2 that is Ca 2؉ -independent and sensitive to bromoenol lactone, associated with the outer mitochondrial membrane. We hypothesize that, under reduced respiratory rate, brain mitochondria release sPLA 2 -IIA that might contribute to cell damage.

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“…Cyctotoxic eVects of LPC and its alkyl homologs are best known from animal cells and have been applied for antitumor therapies (Vogler et al 1991;Chien-Cheng et al 2000). Targets are the biosynthesis of phosphatidylcholine (PC) and several membrane barrier functions (Niewoehner et al 1987;Rustenbeck et al 1996). In plant cells, true signal functions of LPC are detected at concentrations around 1 M, whereas concentrations above 20 M cause toxic eVects at the plasma membrane, P-ATPase is stimulated in the low but inhibited in the high-concentration range (Bellamine and Greppin 1996); at the tonoplast, Na + /H + antiporters are stimulated at the low concentration but membrane leakage is observed at high concentrations (Viehweger et al 2002).…”

Section: Introductionmentioning

confidence: 99%

The signal molecule lysophosphatidylcholine in Eschscholzia californica is rapidly metabolized by reacylation

Schwartze

Roos

2008

Planta

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In cultured cells of California poppy (Eschscholzia californica), lysophosphatidylcholine (LPC) triggers a signal path that finally induces alkaloid biosynthesis. LPC is transiently generated by elicitor-activated phospholipase A(2) of the plasma membrane. Externally added LPC is rapidly acylated by a membrane-bound enzyme that shows the highest specific activity in the purified plasma membrane. The fatty acid incorporated into the sn-2 position of LPC is preferentially linoleic (18:2), which is the most abundant acyl component in the PC species of Eschscholzia cells, but a minor component of the pool of free fatty acids. The fatty acid at the sn-1 position of LPC is less important for substrate specificity. The capacity of LPC acylation by intact cells or isolated plasma membranes by far exceeds the rate of LPC generation by activated phospholipase A(2) and is not limited by the availability of acyl donors. Metabolites other than phosphatidylcholine (PC) were not significantly produced from labeled LPC within 20 min, indicating that lysophospholipases are not significantly contributing to the short-time metabolism of LPC. It is concluded that reacylation to PC is the dominating process in the detoxication of LPC and ensures the transient character of its steady state concentrations, even at maximum phospholipase A(2) activities.

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Relation between accumulation of phospholipase A2 reaction products and Ca2+ release in isolated liver mitochondria

Cited by 21 publications

References 46 publications

Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

Rat Brain Cortex Mitochondria Release Group II Secretory Phospholipase A2 under Reduced Membrane Potential

The signal molecule lysophosphatidylcholine in Eschscholzia californica is rapidly metabolized by reacylation

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