The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Original Article
Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA2 activation
Tomoyuki SatoMasahiro SegawaShuichi SekineKousei Ito
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2019 Volume 44 Issue 11 Pages 811-820

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Abstract

Troglitazone, the first peroxisome proliferator-associated receptor γ agonist developed as an antidiabetic drug, was withdrawn from the market due to idiosyncratic severe liver toxicity.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 (iPLA2)-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 Ca2+ and membrane potential as triggers of iPLA2 activation or MPT induction. As a link between iPLA2 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) Ca2+ release from the mitochondrial matrix was induced prior to troglitazone-induced onset of MPT, (2) released Ca2+ 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 iPLA2 activation might mediate troglitazone-induced MPT.

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© 2019 The Japanese Society of Toxicology
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