Mechanism of Thiazolidinedione-Dependent Cell Death in Jurkat T Cells

Abstract

Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPAR␥-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPAR␥-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone-and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.

α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II

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Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain

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Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

“…Different studies demonstrated that inhibition of complex II governs a direct apoptotic process in neurons through cell-specific pathways. It was recently shown that neurons, which require high levels of energy, are sensitive to complex II-induced OxPhos impairment and this results in a rapid ATP decrease (Mandavilli et al, 2005;Liot et al, 2009;Mbaya et al, 2010), contrary to other cell types, which did not show such a rapid ATP drop in response to complex II inhibition by a SDHC mutant or by the inhibitor thenoyltrifluoroacetate (Senoo-Matsuda et al, 2001;Ishii et al, 2007;Soller et al, 2007;Byun et al, 2008). In neurons, this ATP decrease induced by either 3-nitropropionate, aptenin or a SDHA mutant causes a profound alteration of the intracellular and mitochondrial calcium homeostasis, which then leads to an amplification of mitochondrial ROS formation by complex II and probably by other sources, DC M loss and finally neuronal apoptotic cell death (Liot et al, 2009;Mbaya et al, 2010).…”