Glutaredoxin 2 (Grx2) has been previously shown to link thioredoxin and glutathione systems receiving reducing equivalents by both thioredoxin reductase and glutathione. Grx2 catalyzes protein ...glutathionylation/de-glutathionylation and can coordinate an iron-sulfur cluster, forming inactive dimers stabilized by two molecules of glutathione. This protein is mainly located in the mitochondrial matrix, though other isoforms have been found in the cytosolic and nuclear cell compartments. In the present study, we have analyzed the monomeric and dimeric states of Grx2 under different redox conditions in HeLa cells, and sodium selenite was utilized as the principal oxidizing agent. After selenite treatment, an increased glutathione oxidation was associated to Grx2 monomerization and activation, specifically in the mitochondrial compartment. Interestingly, in mitochondria, a large decline of thioredoxin reductase activity was also observed concomitantly to Grx2 activity stimulation. In addition, Grx2 monomerization led to an increase free iron ions concentration in the mitochondrial matrix, induction of lipid peroxidation and decrease of the mitochondrial membrane potential, indicating that the disassembly of Grx2 dimer involved the release of the iron-sulfur cluster in the mitochondrial matrix. Moreover, sodium selenite-triggered lipid and protein oxidation was partially prevented by deferiprone, an iron chelator with mitochondriotropic properties, suggesting a role of the iron-sulfur cluster release in the observed impairment of mitochondrial functions. Thus, by sensing the overall cellular redox conditions, mitochondrial Grx2 dimers become active monomers upon oxidative stress induced by sodium selenite with the consequent release of the iron-sulfur cluster, leading to activation of the intrinsic apoptotic pathway.
Thioredoxin reductase 2 (TrxR2) is a key component of the mitochondrial thioredoxin system able to transfer electrons to peroxiredoxin 3 (Prx3) in a reaction mediated by thioredoxin 2 (Trx2). In this ...way, both the level of hydrogen peroxide and thiol redox state are modulated. TrxR2 is often overexpressed in cancer cells conferring apoptosis resistance. Due to their exposed flexible arm containing selenocysteine, both cytosolic and mitochondrial TrxRs are inhibited by a large number of molecules. The various classes of inhibitors are listed and the molecules acting specifically on TrxR2 are extensively described. Particular emphasis is given to gold(I/III) complexes with phosphine, carbene or other ligands and to tamoxifen-like metallocifens. Also chemically unrelated organic molecules, including natural compounds and their derivatives, are taken into account. An important feature of many TrxR2 inhibitors is provided by their nature of delocalized lipophilic cations that allows their accumulation in mitochondria exploiting the organelle membrane potential. The consequences of TrxR2 inhibition are presented focusing especially on the impact on mitochondrial pathophysiology. Inhibition of TrxR2, by hindering the activity of Trx2 and Prx3, increases the mitochondrial concentration of reactive oxygen species and shifts the thiol redox state toward a more oxidized condition. This is reflected by alterations of specific targets involved in the release of pro-apoptotic factors such as cyclophilin D which acts as a regulator of the mitochondrial permeability transition pore. Therefore, the selective inhibition of TrxR2 could be utilized to induce cancer cell apoptosis.
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•The mitochondrial thioredoxin system has a key role in redox signaling pathways.•Cancer cells overexpress the thioredoxin system to counteract free radicals production.•Inhibition of thioredoxin reductase 2 activates apoptosis leading to cancer cell death.•Thioredoxin reductase inhibitors mainly target the selenocysteine in the active site.•Delocalized lipophilic cations are able to selectively accumulate in mitochondria.
Abstract
Soy (
Glycine max)
and oats (
Avena sativa
) are plant sources used in milk-alternative beverages. However, protein and lipid constituents of these food matrices can undergo alterations ...during the storage. In this work, a commercial formulation of soy and oat-based beverages were comparatively evaluated. During the 12 months of shelf life and two following months, their phenolic content, antioxidant capacity, lipid peroxidation, protein carbonyl formation and protein breakdown were assessed. Total phenolic content and antioxidant capacity of soy and oat-based beverages were maintained during the entire period of 14 months. Both beverages did not show any increase in spontaneous lipid peroxidation beyond the basal level, however, due to the different content of unsaturated fats, when lipid peroxidation was stimulated, soy exhibited a major peroxidizability with respect to oat beverage. Oxidative alteration of proteins, estimated as carbonyl group formation, presented no increase with respect to the basal levels both in soy and oat beverages for all 14 months. Finally, soy proteins showed a gradual increase of proteolytic activity up until half of the shelf life, while oat did not show significant changes in protein fragmentation. In conclusion, both soy and oat beverages resulted oxidatively stable throughout their storage. We suggest that phytochemicals might guarantee the oxidative stability of the product, possibly in combination with antioxidant bioactive peptides, which already have well-known benefits on human health.
Graphical abstract
Doxorubicin cardiomyopathy is a lethal pathology characterized by oxidative stress, mitochondrial dysfunction, and contractile impairment, leading to cell death. Although extensive research has been ...done to understand the pathophysiology of doxorubicin cardiomyopathy, no effective treatments are available. We investigated whether monoamine oxidases (MAOs) could be involved in doxorubicin-derived oxidative stress, and in the consequent mitochondrial, cardiomyocyte, and cardiac dysfunction.
We used neonatal rat ventricular myocytes (NRVMs) and adult mouse ventricular myocytes (AMVMs). Doxorubicin alone (
, 0.5 μ
doxorubicin) or in combination with H
O
induced an increase in mitochondrial formation of reactive oxygen species (ROS), which was prevented by the pharmacological inhibition of MAOs in both NRVMs and AMVMs. The pharmacological approach was supported by the genetic ablation of MAO-A in NRVMs. In addition, doxorubicin-derived ROS caused lipid peroxidation and alterations in mitochondrial function (
, mitochondrial membrane potential, permeability transition, redox potential), mitochondrial morphology (
, mitochondrial distribution and perimeter), sarcomere organization, intracellular Ca
homeostasis, and eventually cell death. All these dysfunctions were abolished by MAO inhibition. Of note,
MAO inhibition prevented chamber dilation and cardiac dysfunction in doxorubicin-treated mice.
This study demonstrates that the severe oxidative stress induced by doxorubicin requires the involvement of MAOs, which modulate mitochondrial ROS generation. MAO inhibition provides evidence that mitochondrial ROS formation is causally linked to all disorders caused by doxorubicin
and
. Based upon these results, MAO inhibition represents a novel therapeutic approach for doxorubicin cardiomyopathy.