Regulation of the Ca -independent phospholipase A2 in liver mitochondria by changes in the energetic state

Rauckhorst, Adam J.; Broekemeier, Kimberly M.; Pfeiffer, Douglas R.

doi:10.1194/jlr.m043307

Cited by 13 publications

(11 citation statements)

References 58 publications

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“…There are only few publications on the effect of rotenone on iPLA 2 activity in mitochondria. In studies on isolated lung and liver mitochondria, rotenone treatment caused the release of PUFA which was partially sensitive to R-BEL [63, 64]. Our in vivo studies, however, did not document higher levels of free fatty acids or oxygenated free fatty acids in SN of rotenone-treated rats vs control rats.…”

Section: Discussioncontrasting

confidence: 67%

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

Tyurina

Polimova

Maciel

et al. 2015

Free Radical Research

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Exposure to rotenone in vivo results in selective degeneration of dopaminergic neurons and development of neuropathological features of Parkinson's disease. As rotenone acts as an inhibitor of mitochondrial respiratory complex I, we employed oxidative lipidomics to assess oxidative metabolism of a mitochondria-specific phospholipid, cardiolipin, in substantia nigra of exposed animals. We found a significant reduction of oxidizable PUFA-containing cardiolipin molecular species. We further revealed increased contents of mono-oxygenated cardiolipin species at late stages of the exposure. Notably, linoleic acid in sn-1 position was the major oxidation substrate yielding its mono-hydroxy- and epoxy-derivatives whereas more readily “oxidizable” fatty acid residues (arachidonic, docosahexaenoic acids) – remained non-oxidized. Elevated levels of PUFA cardiolipins were detected in plasma of rats exposed to rotenone. Characterization of oxidatively modified cardiolipin molecular species in substantia nirga and detection of PUFA-containing cardiolipin species in plasma may contribute to better understanding of the Parkinson's disease pathogenesis and lead to the development of new biomarkers of mitochondrial dysfunction associated with this disease.

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Section: Discussioncontrasting

confidence: 67%

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

Tyurina

Polimova

Maciel

et al. 2015

Free Radical Research

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“…This activity was subsequently shown to play a facilitating role in occurrence of the mitochondrial permeability transition and to modulate release of cytochrome c from isolated mitochondria [2]. More recently, through use of select combinations of electron transport inhibitors and substrates, we demonstrated that increased activity is not determined by the redox status of any particular electron transport complex, that activation occurs in a graded fashion, and that activation by de‐energization is reversed when an energized state is restored [3]. These regulatory features suggest that this activity is involved in sensing and coordinating cellular bioenergetics and cellular fate.…”

Section: Introductionmentioning

confidence: 91%

The iPLA₂γ is identified as the membrane potential sensitive phospholipase in liver mitochondria

2015

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a b s t r a c tPrevious reports from our lab identified a mitochondrial calcium-independent phospholipase A 2 activity that is activated when the mitochondrial membrane potential is decreased. This activity was demonstrated to influence occurrence of the permeability transition. Originally, this activity was ascribed to the iPLA 2 b protein. Recently, both iPLA 2 b and iPLA 2 c knock out mice have been generated. It has been shown by others that the iPLA 2 c plays a significant role in progression of the permeability transition. In this paper, using the iPLA 2 b and iPLA 2 c knock out mice we show that the membrane potential sensitive activity is the iPLA 2 c.

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“…As a candidate iPLA 2 activator, we suggest mild depolarization because only a 10% decrease in membrane potential (induced by respiratory chain inhibition) is sufficient to activate iPLA 2 by 2-fold (Rauckhorst et al, 2014). As shown in Fig.…”

Section: Discussionmentioning

confidence: 75%

“…It is reported that troglitazone depolarizes mitochondria (Masubuchi et al, 2006) and a drop in mitochondrial membrane potential leads to activation of mitochondrial iPLA 2 (Rauckhorst et al, 2014). To investigate whether depolarization was involved in MPT induction, we assessed the effect of troglitazone on mitochondrial membrane potential.…”

Section: Mild Depolarization Induces Mptmentioning

confidence: 99%

Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA<sub>2</sub> activation

et al. 2019

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-Troglitazone, the first peroxisome proliferator-associated receptor γ agonist developed as an antidiabetic drug, was withdrawn from the market due to idiosyncratic severe liver toxicity. One proposed mechanism by which troglitazone causes liver injury is induction of mitochondrial membrane permeability transition (MPT), which occurs in a calcium-independent phospholipase A2 (iPLA 2)-dependent manner at a concentration of 10 µM. MPT, induced by opening of the MPT pore, leads to the release of cytochrome c and consequent apoptosis or necrosis. In the present study, we aimed to clarify the mechanism of troglitazone-induced MPT in more detail using isolated rat liver mitochondria. We focused on extra-mitochondrial Ca 2+ and membrane potential as triggers of iPLA 2 activation or MPT induction. As a link between iPLA 2 and MPT, we focused on cardiolipin (CL), a unique, mitochondria-specific phospholipid with four acyl chains that affects respiration, the morphology, and other mitochondrial functions. We found that (1) Ca 2+ release from the mitochondrial matrix was induced prior to troglitazone-induced onset of MPT, (2) released Ca 2+ was involved in troglitazone-induced MPT, (3) mild depolarization (approximately 10%) may be a trigger of troglitazone-induced MPT and (4) enhanced decomposition of CL following mitochondrial iPLA 2 activation might mediate troglitazone-induced MPT.

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Regulation of the Ca -independent phospholipase A2 in liver mitochondria by changes in the energetic state

Cited by 13 publications

References 58 publications

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

The iPLA₂γ is identified as the membrane potential sensitive phospholipase in liver mitochondria

Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA<sub>2</sub> activation

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Regulation of the Ca -independent phospholipase A2 in liver mitochondria by changes in the energetic state

Cited by 13 publications

References 58 publications

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease

The iPLA2γ is identified as the membrane potential sensitive phospholipase in liver mitochondria

Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA<sub>2</sub> activation

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The iPLA₂γ is identified as the membrane potential sensitive phospholipase in liver mitochondria