The Thiol-specific Antioxidant Enzyme Prevents Mitochondrial Permeability Transition

Abstract

Mitochondrial swelling and membrane protein thiol oxidation associated with mitochondrial permeability transition induced by Ca 2؉ and inorganic phosphate are inhibited in a dose-dependent manner either by catalase, the thiol-specific antioxidant enzyme (TSA), a protein recently demonstrated to present thiol peroxidase activity, or ebselen, a selenium-containing heterocycle which also possesses thiol peroxidase activity. This inhibition of mitochondrial permeability transition is due to the removal of mitochondrial-generated H 2 O 2 which can easily diffuse to the extramitochondrial space. Whereas ebselen required the presence of reduced glutathione as a reductant to grant its protective effect, TSA was fully reduced by mitochondrial components. Decrease in the oxygen concentration of the reaction medium also inhibits mitochondrial permeabilization andmembraneproteinthioloxidation,inaconcentrationdependent manner. The results presented in this report confirm that mitochondrial permeability transition induced by Ca 2؉ and inorganic phosphate is reactive oxygen species-dependent. The possible importance of TSA as an intracellular antioxidant, avoiding the onset of mitochondrial permeability transition, is discussed in the text.

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

“…1, trace 3) has a similar effect to GSH in preventing VP-16-induced mitochondrial swelling. The fact that the effects of VP-16 are prevented by Asc, GSH and NEM, but not by DHA and GSSG, suggests the involvement of oxidative events, as reported to other MPT inducers whose action mechanism has been recognized to be mediated by dithiol and pyridine nucleotides oxidation [30,31].…”

“…Moreover, the MPT possesses at least two redox-sensitive sites, one of them in equilibrium with GSH of mitochondrial matrix and another that can be directly activated by ROS [30]. Therefore, in addition to the oxidation of membrane protein sulfhydryl groups, the oxidation of both GSH and NAD(P)H of mitochondrial matrix [30], followed closely by an increase in the mitochondrial Ca 2 + and ROS generation within mitochondria (or a decreasing in their detoxification), contributes to the MPT induction, as shown by studies with several MPT inducers, including tert-butylhydroperoxide [39][40][41][42] and inorganic phosphate [31,43]. Besides the generation of ROS, NO can also act on mitochondria amplifying the signals promoting the MPT [44,45].…”

Overexpression of CYP2E1 in Mitochondria Sensitizes HepG2 Cells to the Toxicity Caused by Depletion of Glutathione

“…Mitochondrial permeability transition and mitochondrial membrane potential are markers for mitochondrial damage and dysfunction (38 -40). Mitochondrial dysfunction caused by ROS can lead not only to necrosis by depleting ATP but also to apoptosis by inducing the release of cytochrome c, which activates caspases together with other mitochondrial factors such as Apaf-1 (41,42). We determined the mitochondrial membrane potential in cells treated with BSO.…”

The mitochondrial permeability transition pore and its role in cell death

“…On the other hand, uncoupling of the respiratory chain, used to manipulate membrane potential (above), leads to increased O # − production [136]. Experiments employing uncoupling agents at various O # tensions, thereby varying O # − formation, have yielded conflicting results, suggesting a major [146] or minor [147] contribution of oxidative stress to uncoupler-induced pore activation. It is also possible that the energy-linked transhydrogenase provides a link between potential and pore activity.…”