Home Chairs: Flavia Meotti, PhD, Universidade de São Paulo, Brazil & Gerardo Ferrer-Sueta, PhD, Universidad de la República, Uruguay
More than three decades have elapsed since the formal naming as Peroxiredoxins of the then new family of peroxidases, and in the interim the number of their known functions has grown. From their original antioxidant role, Peroxiredoxins have shown the roles of the sensing of oxidants, chaperones/holdases and, more recently, in redox signaling, by relaying of electrons via thiol disulfide reactions with target molecules. The knowledge on Peroxiredoxin biochemistry and physiology has expanded extremely fast, and that growth has involved research groups of our region, such as those of Luis Netto and Ohara Augusto in Brazil and those of Rafael Radi and Ana Denicola in Uruguay. That pioneer Peroxiredoxin research in the region has produced new generations of young researchers whose names appear in the more than a dozen annual articles that have consistently been published by, or with the collaboration, of South American groups in the past decade. The scope of our proposed Symposium on Peroxiredoxins is to encompass the breadth of research including as senior speakers one addressing a very basic enzymological approach of Peroxiredoxin function and the other one presenting the latest results of Peroxiredoxin involvement in cancer. We hope that the proposed Symposium on Peroxiredoxins will be an optimal opportunity for researchers to meet and share their findings from the basic biochemistry to the physiological roles and clinical applications of peroxiredoxins.
Symposia Abstracts:
Interactions of 1-Cys Peroxiredoxins and Ascorbate in Pathogenic Microorganisms’ Response to Hydroperoxides and Seed Biology
Bruce Morgan, PhD, Saarland University, Germany
Interactions Between Peroxiredoxins and Other Mitochondrial Compounds: Kinetics, Reaction Mechanisms and Effects on Hyperoxidation
Madia Trujillo, MD, PhD, Universidad de la República, Uruguay
Peroxiredoxins (Prdxs) are thiol-dependent peroxidases that catalyze the reduction of different hydroperoxides. Mitochondria, which are main sources of these oxidants, express Prdx3 and Prdx5. According to kinetic estimations, Prdx3 reduces most mitochondrial hydrogen peroxide while both enzymes are major peroxynitrite reductases. Additionally, Prdx3 is rapidly oxidized and hyperoxidized by free FA-OOH. Phospholipid-bound FA-OOH, on the contrary, marginally hyperoxidizes Prdx3, but leads to a decrease in its activity. Notably, the presence of hyperoxidized Prdx3 at the plasmatic membrane is a hallmark of ferroptosis, a form of cell death characterized by membrane lipoperoxidation. The mechanism of this Prdx3 modification and translocation is currently unknown. Furthermore, Prdx3 gets thiolated by the main low molecular weight thiols present in the mitochondria, namely glutathione (GSH) and coenzyme A (CoA). The mechanisms of Prdx3 thiolation by CoA are thiol disulfide exchange reactions and also the reaction of the thiolate of CoA with the sulfenic acid at the peroxidatic Cys of the oxidized enzyme. Accordingly, CoA protected Prdx3 from hyperoxidation. Thiolation by GSH, however, only occurs through thiol-disulfide exchange at physiological concentrations. Thiolation by GSH and by CoA occurs at all the three Cys residues of Prdx3. The thiolated forms of Prdx3 are reduced by mitochondrial reducing systems glutaredoxin 2 (for Prdx3-SG) and thioredoxin 2 (for Prdx3-SCoA). Additionally, we investigated the reactions of Prdx5 with FA-OOH. Prdx5 rapidly reacts with free FA-OOH, in a reversible process with a koff = 10 s-1 and kon = 10e6 M-1s-1 at pH 7.4 and 25°C. The oxidants lead to Prdx5 oxidation, but the enzyme is very resistant to hyperoxidation, either by hydrogen peroxide (both in the absence or presence of CO2) and free FA-OOH. Thus, in mitochondria forming low fluxes of free FA-OOH (~ 1 nM/s), Prdx3 (that reduces these compounds with rate constants in the 10e8 M-1s-1 range) is expected to catalytic reduce most free FA-OOH. However, in mitochondria forming high fluxes of free FA-OOH (~100 nM/s), Prdx3 is expected to be inactivated due to hyperoxidation while Prdx5 contribution to free FA-OOH reduction would increase.
Chairs: Francisco RM Laurindo, MD, PhD, Heart Institute (Incor), University of Sao Paulo School of Medicine and Lei Wang, PhD, State Key Laboratory of Biomacromolecules
The Endoplasmic Reticulum (ER) is the largest cellular organelle and exerts crucial functions in protein folding and processing, lipid metabolism, calcium regulation, among many others. ER-dependent redox processes are central to the regulation of ER activities, but also extend to several related extra-ER activities. These include the increasingly evident regulation of extracellular redox processes by the ER, particularly the secretion and cell-surface translocation of ER thiol oxidoreductases, which mediates intercellular redox communication related to cell adhesion processes, thrombosis, platelet adhesion, mechanoadaptation and vascular remodeling. In addition, a number of other intracellular functions, including Nox regulation, cytoskeleton organization and cancer cell survival, depend on ER-associated redox processes, including in particular the recently described reflux of ER proteins to the cytosol. The ER also establishes contacts with plasma membrane, mitochondria, peroxisomes, lysosomes, endosomes and other organelles, allowing extensive communications at least in part related to redox pathways, merging with calcium exchange. The ER redoxome, thus, comprises an extensive network of small molecule oxidants (such as hydrogen peroxide from the ER lumen), thiol oxidoreductases (Ero1 and PDI family proteins) and thiol proteins (e.g., Prx4, Gpx7, Gpx8), in addition to glutathione exchange pathways. This symposium aims to discuss state-of-the-art developments regarding mechanisms and implications of ER-dependent redox processes. This should be a valuable opportunity to raise the awareness of this area, which is to some extent yet emerging in the redox community. Moreover, given the broadness and importance of the theme, as well as the excellence of speakers, the symposium is likely to motivate many other investigators of the redox community towards collaborative efforts and inter-disciplinary scientific progress.
Symposia Abstracts:
The ER Redoxtasis: From Basic Research to the Intervention of Aging and Diseases
Lei Wang, PhD, State Key Laboratory of Biomacromolecules
The unique oxidizing environment of the endoplasmic reticulum (ER) facilitates the oxidative folding of secretory and membrane proteins, which are rich in disulfide bonds. The endoplasmic reticulum (ER) oxidoreductin-1α (Ero1α) and protein disulfide isomerase (PDI) constitute the pivotal oxidative protein folding pathway in the ER, and the byproduct of this process is hydrogen peroxide. Oxidative protein folding fidelity and ER redox homeostasis (redoxtasis) are maintained by both the precise control of Ero1α oxidase activity and the division of labor between PDI family members. Deregulated Ero1α-PDI functions contribute to aging and various diseases including cancers, thrombosis and inflammation. Our recent work identified two small molecule compounds, from an FDA-approved drug library, as highly selective Ero1α-PDI inhibitor, which providing new strategies for combating diseases associated with ER redox dysregulation.
A Redox-Sensitive Mechanism Controls ER Protein Redistribution During Stress
Aeid Igbaria, PhD, Ben-Gurion University of the Negev
Maintenance of endoplasmic reticulum (ER) proteostasis is essential for cell survival under stress. In addition to established quality control pathways, ER-to-cytosol signaling (ERCYS) enables ER-resident proteins to relocalize to the cytosol and support adaptive responses. However, how this process is regulated and how it connects to cellular stress outcomes remains incompletely understood. Here, we identify the cellular redox environment as a central regulator of ER protein reflux. We show that this process operates within a defined redox-sensitive stress window: under mild stress conditions, protein reflux is enhanced and supports cell adaptation, whereas more severe or reductive conditions suppress reflux despite strong activation of stress signaling pathways. These findings indicate that redox balance, rather than stress intensity alone, dictates whether ERCYS is engaged. We further demonstrate that both ER-resident and cytosolic chaperone systems are influenced by redox changes, highlighting coordinated regulation across compartments. Disruption of this redox balance limits protein reflux and alters the cellular response to stress. Importantly, when redox conditions inhibit ER protein reflux, cells shift toward alternative pathways associated with ER dysfunction and increased cell death. Together, our results position redox regulation as a key switch controlling ER protein redistribution and determining whether cells mount adaptive or detrimental responses under stress.
Chairs: Sayuri Miyamoto, PhD, University of Sao Paulo and Homero Rubbo, PhD, Facultad de Medicina, Universidad de la República
Oxidative stress (OxS) and lipid-derived mediators are increasingly recognized as critical regulators in the development and progression of chronic diseases, including atherosclerosis and cancer. Rather than acting solely as damaging agents, oxidative stress markers and lipid oxidation products can exert protective or pathogenic effects depending on context, timing, and cellular environment. This symposium will highlight recent advances that elucidate the complex and often dual roles of oxidative stress in modulating inflammation, immune cell metabolism, and tumorigenesis. By integrating mechanistic studies from experimental models with large-scale epidemiological findings, the session will provide a multidimensional view of how redox-sensitive pathways and lipid peroxidation products influence disease initiation and trajectory. Specific focus will be given to the modulation of macrophage function in atherosclerosis and the time-dependent relationship between systemic oxidative stress and colorectal cancer risk.
Symposium Objectives:
This symposium will be particularly relevant to those interested in understanding how oxidative stress and lipid signaling intersect to influence chronic disease risk and progression.
Symposia Abstracts:
Targeting Lipid Biomarkers in Cancer Through Mass Spectrometric AnalysisTargeting Lipid Biomarkers in Cancer Through Mass Spectrometric Analysis
Ginger Milne, PhD, University of Alabama
ATHEROPROTECTIVE ACTION OF NITRO-FATTY ACIDS IN METABOLIC DYSFUNCTION
Gustavo Bonacci, PhD, Universidad Nacional de Córdoba
Metabolic diseases, including diabetes and obesity, constitute a major global epidemic and are significant risk factors for numerous cardiovascular pathologies, such as atherosclerosis. Nitro-fatty acids (NO2-FA), have demonstrated a protective role against metabolic disease through modulation of inflammatory signaling pathways of NF-kB, TLR4 and PPARgamma. These endogenously generated electrophilic fatty acids, formed through nitric oxide–related redox chemistry in the gastrointestinal tract or during inflammatory processes, regulate cell signaling via cysteine nitroalkylation. To date, we know that NO2-FA administration in experimental models of atherogenesis (ApoE-/- mice) reduces the size and development of atheromatous plaque; however, how NO2-FA affect lipid metabolism in atherosclerosis has not been studied in detail. Alterations in lipid metabolism further accelerate disease progression by enhancing lipid accumulation within monocytes and macrophages, thereby fostering foam cell formation and sustaining inflammatory signaling. We have recently demonstrated that NO2-FA modulates lipid droplet accumulation in macrophage and cellular cholesterol content by limiting CD36-mediated oxLDL uptake and enhancing cholesterol efflux. Furthermore, NO2-FA induces profound changes in monocytes genes expression. Altogether, these findings show that NO2-FA attenuates pro-atherogenic programs in macrophages and monocytes at early stages of disease, reducing expression of pro-inflammatory markers (LRP1 and CD11c), decreasing monocyte–endothelial adhesion, and inducing a rapid transcriptional reprogramming in circulating monocytes. These findings indicate that NO2-FA modulate lipid metabolism in immune cells; suggesting a potential therapeutic role in preventing early atherosclerotic plaque development.
Chairs: Antonio Marcus de Andrade Paes, PhD, Universidade Federal do Maranhao and Andrés Trostchansky, PhD, Facultad de Medicina, Universidad de la República
Platelets play a fundamental role in hemostasis and thrombosis, with their activation and aggregation tightly regulated by redox signaling. Emerging evidence highlights the influence of redox metabolism on platelet function in both physiological and pathological conditions, including cardiovascular disease, inflammation, and oxidative stress-related disorders. This symposium will explore the intricate redox mechanisms that govern platelet activation and aggregation, with a particular focus on the contributions of mitochondria and other organelles, such as peroxisomes and the endoplasmic reticulum.
Recent studies have underscored the role of reactive oxygen species (ROS) and redox enzymes in modulating platelet responses, revealing new opportunities for targeting redox pathways in antiplatelet therapy. We will discuss how oxidative modifications of key platelet proteins affect their function and how redox-based signaling pathways intersect with classical platelet activation cascades. Furthermore, this session will highlight the latest advancements in the development of antiplatelet drugs designed to target redox mechanisms, offering novel therapeutic strategies for thrombotic diseases.
By integrating recent discoveries with translational perspectives, this symposium aims to provide a comprehensive understanding of redox biology in platelets. It will foster discussions on emerging therapeutic applications and future research directions, making it particularly relevant for researchers in platelet biology, redox signaling, cardiovascular health, and drug development.
Symposia Abstracts:
Mitochondrial Redox Signaling and Organelle-Targeted Strategies: Balancing Pro-Thrombotic Environmental Risks with Natural and Synthetic Antiplatelet Therapies
Andrés Trostchansky, PhD, Facultad de Medicina, Universidad de la República
Cardiovascular diseases remain the global leading cause of death, driven by platelet activation and thrombus formation, processes that are fundamentally governed by intricate redox signaling and organelle function. Emerging environmental threats, such as circulating microplastics and nanoplastics (PS-NPs), have been identified as unrecognized pro-thrombotic factors that disrupt this balance. These particles rapidly associate with human platelets, inducing marked morphological changes and a robust pro-coagulant phenotype characterized by CD63 externalization and dense fibrin clot formation. This environmental oxidative stress highlights the urgent need for redox-based therapeutic interventions. Natural products offer a potent defense; for instance, nitrated fatty acids (NO2-FA) derived from tomato pomace exert significant antiplatelet effects by modulating activation markers and inhibiting aggregation induced by agonists like TRAP-6 and collagen. Complementing these natural strategies, synthetic chemistry allows for the development of targeted redox modulators. A series of synthetic ortho-carbonyl hydroquinone derivatives has been shown to inhibit platelet aggregation in a non-competitive manner, reducing the expression of P-selectin and the activation of glycoprotein IIb/IIIa without inducing cytotoxicity. Because platelets rely on fully functional mitochondria to drive activation, this organelle represents a primary target for redox-centered drug development. By synthetically enhancing the natural compound magnolol with a triphenylphosphonium cation (MGN4), researchers have achieved a three-fold increase in antiplatelet efficacy through the specific modulation of mitochondrial respiration and bioenergetic fluxes. Together, these findings underscore the critical role of mitochondrial and organelle-specific redox pathways in both the pathology of plastic-induced thrombosis and the advancement of novel, high-affinity antiplatelet strategies
Biophysical changes in oxidised collagen are associated with increased platelet responsiveness
Renato Simoes Gaspar, MD, PhD, University of Campinas
The excessive production of oxidants resulting from oxidative imbalance contributes in various ways to the pathophysiology of cardiovascular diseases (CVDs). Platelets contribute to this process through their aggregation, adhesion, and thrombus formation capacity. Platelet adhesion and thrombus formation depend on endothelial injury that exposes the subendothelial extracellular matrix (ECM), which is rich in type I collagen - a long-lived protein. Although the direct pro-thrombotic effects of different reactive oxygen species on platelets are known, it remains unclear whether non-enzymatic collagen oxidation contributes to platelet hyperreactivity. Interestingly, it was shown recently that, upon rupture, collagen itself is an oxidant-generating source. Our group is investigating how (or whether) direct, non-enzymatic, oxidation of collagen molecules control platelet responses. First we show using synchrotron radiation circular dichroism that oxidised collagen is as thermo-stable as non-oxidised fibres. Using atomic force microscopy, we identify distinct 'knot-like' structures in oxidised collagen. Oxidised fibres accumulate crosslinks and are more rigid than control collagen. Such biophysical changes translate into a 7-fold increase in platelet aggregation induced by oxidised collagen when compared to control collagen. This effect is reproducible with different oxidation protocols – i.e. using hydrogen peroxide or Fenton reaction. Interestingly, oxidised collagen-stimulated platelets are less sensitive to acetylsalicilic acid (AAS), despite normal thromboxane B2 production. This lack of sensitivity to AAS is dependent on oxidant production. Overall, we provide novel pathophysiological cues leading to platelet hyperactivation in pro-oxidant environments. By linking changes of collagen molecules and their repercussion to platelets, we speculate that biochemical changes induced by oxidation may lead to dysfunctional cellular responses through structural, biophysical modulation of the targeted protein. Oxidised collagen may pose as a novel player in cardiovascular diseases.
Chairs: Carolina Lorente, PhD, Universidad Nacional de La Plata, CONICET and Erick Leite Bastos, PhD, Universidade de São Paulo
Exposure to the sun is not always harmful to living beings, which depend on photosynthesis for life to be possible. However, it is well-known that exposure of living systems to solar or artificial electromagnetic radiation causes oxidative stress, since the interaction of suitable molecules with electromagnetic radiation generates reactive species through photoinduced electron transfer reactions that, although they are essential for generating energy in plants, can cause damage to biomolecules relevant for physiological functions.
The mechanism involved in photoinduced electron transfer can be either direct or indirect, depending on which molecule is ultimately damaged. During direct mechanisms, the molecule absorbs radiation and is transformed into reactive species yielding oxidation products. On the contrary, during indirect mechanisms, the absorbing molecule is excited to higher energy states and reacts with a second molecule or molecular oxygen to form reactive species, which in a subsequent step reacts with surrounding molecules to oxidize them.
In living organisms, almost all biomolecules are susceptible to oxidation, through direct and indirect mechanisms. The main targets for photoinduced damage are proteins, especially those present in eyes and skin. The oxidation of proteins can result in oxidation of amino acids, fragmentation, generation of dimers and aggregates, loss of structure and function. Also, DNA molecules can be oxidized by radiation, generating mutations which are related to the development of skin cancer, among which melanoma should be highlighted, and are directly related to sun exposure. This symposium will present studies related to the damage caused by electromagnetic radiation, especially due to sun exposure. The proposed speakers are experts in the subject and will present to the audience evidence about the damage caused by photoinduced electron transfer.
Symposia Abstracts:
Singlet oxygen-mediated damage to disulfides and proteins
Michael Davies, PhD, Panum Institute, University of Copenhagen
Disulfide bonds are critical determinants of protein structure, with modifications of these linkages associated with a loss of function. We hypothesized that singlet oxygen (1O2), a key intermediate in photochemical reactions would react rapidly with disulfides and result in selective oxidation of some protein disulfides. Kinetic data for reaction of 1O2 with disulfides were obtained from time-resolved 1270 nm phosphorescence experiments. Stern-Volmer plots showed a large variation (~10(3)) in the quenching rate constants with different disulfides (k ~10(7) - 10(4) M-1s-1). Mass spectroscopic analyses showed formation of mono- and di-oxygenated products via reactive zwitterion intermediates [–S+(OO-)-S-] and solvent effects consistent with 1O2 damage. These data indicate that some disulfides are selectively modified and might impact protein structure and function. This has been examined in two mitochondrial complexes that contain alpha-lipoic acid bound at lysine residues, with this disulfide species being responsible for complex activity. Alpha-keto glutarate dehydrogenase (KGDH) plays a rate-determining role in the tricarboxylic acid cycle, and pyruvate dehydrogenase (PDC) controls cellular glucose metabolism. Dysfunction of these complexes has profound impacts on energy metabolism and results in metabolic diseases. Exposure of KGDH and PDC to 1O2 resulted in a loss of complex activity and protein aggregation with this being modulated by the addition of free lipoic acid and lipoamide. LC-MS/MS peptide mass mapping showed modification of both alpha-lipoic acid (6-55% modification) and sidechain modification at multiple Met, Trp, His and Tyr residues (modification extents of 20-50%). Structure modelling indicates modifications across all complex subunits, within functional domains, and at multimer interfaces. These data suggest that damage at multiple sites contributes to the overall loss of activity. Overall, these data indicate that KGDH and PDC are susceptible to 1O2-induced damage, with potential effects on cellular glucose metabolism. References: Free Radic Biol Med (2023) 207, 320-9; Free Radic Biol Med (2024) 224, 723-9; Free Radic Biol Med (2025) 234, 19-33
Degradation of Biomolecules Photoinduced by Pterins: a Model to Understand Type I Photosensitized Oxidations
Andrés Héctor Thomas, PhD, Universidad Nacional de La Plata
Chairs: Paola Corti, PhD, University of Maryland and Jesus Tejero, PhD, University of Pittsburgh
Heme proteins are pivotal for the biology of reactive oxygen and nitrogen species (ROS/RNS). Through their role in oxygen transport and delivery, oxidative phosphorylation, and the generation (and scavenging) of ROS/RNS, these proteins appear in almost every biological free radical-related pathway. Heme proteins include some of the most researched proteins in biology -myoglobin and hemoglobin. Despite the longstanding interest in heme proteins, novel vertebrate heme proteins -neuroglobin, cytoglobin, androglobin- have been discovered in the last 25 years, and the known globins have been found in unsuspected tissues and cellular locations, challenging our existing knowledge. In this session we focus on recent advances that challenge the general conceptions about the role of heme proteins in chemical biology, from roles in development to vascular biology, light sensing and beyond
Symposia Abstracts:
How heme dictates NO versus ROS release by NO synthases and how the NO regulates cell Catalase function in a surprising way
Dennis Stuehr, PhD, Cleveland Clinic
NO synthases (NOS) are heme-containing proteins that evolved to generate NO, but as redox enzymes, they also can generate ROS, and the degree to which they do so is a topic of biomedical interest. This presentation will compare the relative capacities of the three NOS isoforms to generate NO and ROS, the roles and relative importance of their flavin, heme, and tetrahydrobiopterin cofactors in catalyzing NO and ROS formation, and will outline the cell biological circumstances that tip the scale towards ROS generation. The presentation will also describe how NO released by NOS can regulate catalase maturation to its functional heme-containing form in a surprising way, thereby controlling catalase capacity to provide cellular antioxidant activity against H2O2.
Mitochondrial iron transport and erythropoiesis--lessons from the zebrafish and broader questions
Yvette Yien, PhD, University of Pittsburgh
While iron and heme metabolism are known to play an essential role in erythroid biology, understanding of their functions is generally restricted to their roles in hemoglobin production. Here, we describe work using the zebrafish system to dissect the role of mitochondrial iron in erythropoietic development. We found that mfrn1 embryos, which have a defect in erythroid mitochondrial iron transport, had severely decreased erythroid cell number caused by cell cycle arrest at G2/M. They had enlarged nuclei, suggesting a mitotic defect. Iron supplementation rescued the cell cycle defect, implicating mitochondrial iron deficiency as its cause. The cell cycle defect was specific to terminally differentiating erythroid cells. Further, mfrn1 deficient erythroid cells persistently express markers that are more typical of earlier erythropoiesis. These data are consistent with a model in which mitochondrial iron transport facilitates development of early erythroid progenitors and for the completion of erythropoiesis by facilitating mitosis in the terminal cell cycles.
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