scholarly journals Unique Cellular and Biochemical Features of Human Mitochondrial Peroxiredoxin 3 Establish the Molecular Basis for Its Specific Reaction with Thiostrepton

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 150
Author(s):  
Kimberly J. Nelson ◽  
Terri Messier ◽  
Stephanie Milczarek ◽  
Alexis Saaman ◽  
Stacie Beuschel ◽  
...  
Keyword(s):  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Wild Type ◽  
Cellular Models ◽  
Chemotherapeutic Approach ◽  
Promising Target ◽  
Redox Responsive ◽  
Catalytic Cysteine ◽  
Increased Sensitivity ◽  
Peroxiredoxin 3

A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H2O2). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1–5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy.

Abstract 373: Manganese Superoxide Dismutase: A Novel Mediator of Heart Failure Development and Progression

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sumitra Miriyala ◽  
Mini Chandra ◽  
Jonathan Fox ◽  
Christopher Kevil ◽  
Wayne Orr ◽  
...  
Keyword(s):  
Manganese Superoxide Dismutase ◽  
Primary Source ◽  
Early Mortality ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Wild Type ◽  
Constitutive Activation ◽  
Manganese Superoxide ◽  
Rate Of Oxygen Consumption ◽  
In Cells

Constitutive activation mitochondrial reactive oxygen species (ROS) has been implicated in both the pathogenesis and the progression of cardiovascular disease. Absence of SOD2 (gene that encodes MnSOD) is found to be embryonic lethal in animal models due to impairment of mitochondrial function, most noticeably in the heart. In our earlier investigation, we have shown that the MnSOD mimetic, distributes 3-fold more in mitochondria than in cytosol. The exceptional ability of MnSOD mimetic to dismute O 2 •- parallels its ability to reduce ONOO– and CO3–. Based on our earlier reports, we have generated mice that specifically lack MnSOD in cardiomyocytes (Mhy6-SOD2 Δ ). These mice showed early mortality ~4 months due to cardiac mitochondrial dysfunction. Oxidative phosphorylation (OXPHOS) in mitochondria is the predominant mode for O 2 consumption in cells, and the mitochondria are the primary source of ROS in cells due to leaked electrons. FACS analyses using Mito-Tracker Green indicated that the mass of mitochondria per cell was slightly decreased in the Mhy6-SOD2 Δ to the wild type. The rate of oxygen consumption per cells was significantly lower in Mhy6-SOD2 Δ cardiomyocytes than that in wild type. The most noticeable difference in the O 2 consumption was found in the presence of FCCP (H+ ionophore / uncoupler). Remarkably, while the FCCP treatment increased O 2 consumption in wild type, the treatment showed no effect on the O 2 consumption in the Mhy6-SOD2 Δ cardiomyocytes. The result indicated that the low basal OXPHOS activity in Mhy6-SOD2 Δ was due to unusually low OXPHOS potential.

scholarly journals Featured Article: Accelerated decline of physical strength in peroxiredoxin-3 knockout mice

2016 ◽  
Vol 241 (13) ◽  
pp. 1395-1400 ◽  
Author(s):  
Yong-Gang Zhang ◽  
Li Wang ◽  
Tomonori Kaifu ◽  
Jingmin Li ◽  
Xiaoyan Li ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Energy Supply ◽  
Skeletal Muscles ◽  
Oxidative Status ◽  
Oxygen Species ◽  
Wild Type ◽  
Physical Strength ◽  
Mitochondrial Dna Copy Number ◽  
In The Wild ◽  
Peroxiredoxin 3

As a member of peroxiredoxin family, peroxiredoxin-3 plays a major role in the control of mitochondrial level of reactive oxygen species. During the breeding of experimental mice, we noticed that the peroxiredoxin-3 knockout mice were listless with aging. In the present study, we compared the swimming exercise performance and oxidative status between peroxiredoxin-3 knockout mice ( n = 15) and wild-type littermates ( n = 15). At the age of 10 months, the physical strength of peroxiredoxin-3 knockout mice was much lower than the wild-type littermates. Increased oxidative damage and decreased mitochondrial DNA copy number of the animal skeletal muscles were observed in peroxiredoxin-3 knockout mice as compared to that in the wild-type littermates. In addition, we found increased apoptotic cells in the brains of peroxiredoxin-3 knockout mice. Our results suggest that the deficiency of peroxiredoxin-3 induces accelerated oxidative stress and mitochondrial impairment, resulting in the decrease of energy supply and cellular activities. Peroxiredoxin-3 might be involved in the inhibition of aging process.

scholarly journals TLR2 signaling pathway combats Streptococcus uberis infection by inducing production of mitochondrial reactive oxygen species

2019 ◽  
Author(s):  
Bin Li ◽  
Zhixin Wan ◽  
Zhenglei Wang ◽  
Jiakun Zuo ◽  
Yuanyuan Xu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Signaling Pathways ◽  
Host Defense ◽  
Proinflammatory Cytokines ◽  
Mammary Glands ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Pathological Changes ◽  
Wild Type ◽  
Streptococcus Uberis

AbstractMastitis caused by Streptococcus uberis is a hazardous clinical disease in dairy animals. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2−/− and TLR4−/− mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage and bacterial count in mammary glands. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S. uberis infection. In MECs, TLR2 detected S. uberis infection and induced mitochondrial reactive oxygen species (mROS) to assist host control of secretion of inflammatory factors and elimination of intracellular S. uberis. Our results demonstrate that TLR2-mediated mROS have a significant effect on S. uberis-induced host defense responses in mammary glands as well as MECs.Author summaryS. uberis contributes significantly to global mastitis and remains a major obstacle for inflammation elimination due to its ability to form persistent infection in mammary tissue. The Toll-like receptor (TLR) family plays a significant role in identifying infections of intracellular bacteria and further triggering inflammatory reactions in immune cells. However, the detailed molecular mechanism by which TLR is regulated, and whether MECs, as the main cells in mammary gland, are tightly involved in these processes is poorly understood. Here, we used S. uberis to infect mammary glands of wild type, TLR2−/−, TLR4−/− mice and MECs to assess pathogenesis, proinflammatory cytokines, ROS as well as mROS levels during infection. We found that during S.uberis infection, it is TLR2 deficiency that induced more severe pathological changes through MyD88-mediated signaling pathways. In addition, our work demonstrates that mROS mediated by TLR2 has an important role in host defense response to combat S. uberis infection in mammary glands as well as MECs.

scholarly journals Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Linda Rubinstein ◽  
Ann-Sofie Schreurs ◽  
Samantha M. Torres ◽  
Sonette Steczina ◽  
Moniece G. Lowe ◽  
...  
Keyword(s):  
Simulated Microgravity ◽  
Cytokine Expression ◽  
Hindlimb Unloading ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Wild Type ◽  
Mitochondrial Ros ◽  
Cytokine Milieu ◽  
The Central Nervous System ◽  
Induced Changes

AbstractIsolation on Earth can alter physiology and signaling of organs systems, including the central nervous system. Although not in complete solitude, astronauts operate in an isolated environment during spaceflight. In this study, we determined the effects of isolation and simulated microgravity solely or combined, on the inflammatory cytokine milieu of the hippocampus. Adult female wild-type mice underwent simulated microgravity by hindlimb unloading for 30 days in single or social (paired) housing. In hippocampus, simulated microgravity and isolation each regulate a discrete repertoire of cytokines associated with inflammation. Their combined effects are not additive. A model for mitochondrial reactive oxygen species (ROS) quenching via targeted overexpression of the human catalase gene to the mitochondria (MCAT mice), are protected from isolation- and/or simulated microgravity-induced changes in cytokine expression. These findings suggest a key role for mitochondrial ROS signaling in neuroinflammatory responses to spaceflight and prolonged bedrest, isolation, and confinement on Earth.

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