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Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA 2 activation.
- Source :
-
The Journal of toxicological sciences [J Toxicol Sci] 2019; Vol. 44 (11), pp. 811-820. - Publication Year :
- 2019
-
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- Troglitazone, the first peroxisome proliferator-associated receptor γ agonist developed as an antidiabetic drug, was withdrawn from the market due to idiosyncratic severe liver toxicity.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 (iPLA <subscript>2</subscript> )-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 <superscript>2+</superscript> and membrane potential as triggers of iPLA <subscript>2</subscript> activation or MPT induction. As a link between iPLA <subscript>2</subscript> 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 <superscript>2+</superscript> release from the mitochondrial matrix was induced prior to troglitazone-induced onset of MPT, (2) released Ca <superscript>2+</superscript> 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 <subscript>2</subscript> activation might mediate troglitazone-induced MPT.
- Subjects :
- Animals
Male
Membrane Potential, Mitochondrial drug effects
Mitochondria, Liver metabolism
Mitochondria, Liver physiology
Mitochondrial Permeability Transition Pore
Rats, Wistar
Calcium metabolism
Hypoglycemic Agents pharmacology
Mitochondria, Liver drug effects
Mitochondrial Membrane Transport Proteins metabolism
Phospholipases A2, Calcium-Independent metabolism
Troglitazone pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1880-3989
- Volume :
- 44
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of toxicological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 31708537
- Full Text :
- https://doi.org/10.2131/jts.44.811