Peroxiredoxin III, a Mitochondrion-specific Peroxidase, Regulates Apoptotic Signaling by Mitochondria

Chang, Tong‐Shin; Cho, Chun‐Seok; Park, Sunjoo; Yu, Shiqin; Kang, Sang Won; Rhee, Sue Goo

doi:10.1074/jbc.m407707200

Cited by 348 publications

(279 citation statements)

References 84 publications

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“…Decreased mitochondrial Trx-2 in DT40 chicken B cells increased oxidants and caused spontaneous apoptosis (175). Similarly, decrease in the Trx-2-dependent peroxidase Prx3 increased H 2 O 2 and sensitized HeLa cells to staurosporine-or TNF-␣-induced apoptosis (26). Increased abundance of Prx3 also protected against apoptosis caused by H 2 O 2 (205).…”

Section: Oxidative Stress As a Disruption Of Redox Signaling And Controlmentioning

confidence: 94%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,020

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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Section: Oxidative Stress As a Disruption Of Redox Signaling And Controlmentioning

confidence: 94%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,020

839

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“…It is noteworthy that PRXVI possesses only one Cys residue in the active site, while other PRXs contain 2‐Cys PRXs 142. The intramolecular disulfide of 2‐Cys PRXs is reduced specifically by electrons provided by TRXs, which are then regenerated by TRX reductase at the expense of NADPH,143 thus restoring the catalytic activity.…”

Section: Regulatory Reactive Oxygen and Nitrogen Species Enzymes Exprmentioning

confidence: 99%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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“…4D and Fig. S6C): HMOX1, XIAP, PRDX3, CP, Crystallin, and a putative member of the glutathione peroxidase family (GPX8) (23)(24)(25)(26)(27)(28).…”

Section: Hif2␣ Deficiency Activates P53 By Enhancing Ros Accumulationmentioning

confidence: 99%

HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses

Bertout

Majmundar

Gordan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

178

163

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Approximately 50% of cancer patients receive radiation treatment, either alone or in combination with other therapies. Tumor hypoxia has long been associated with resistance to radiation therapy. Moreover, the expression of hypoxia inducible factors HIF1␣ and/or HIF2␣ correlates with poor prognosis in many tumors. Recent evidence indicates that HIF1␣ expression can enhance radiation-induced apoptosis in cancer cells. We demonstrate here that HIF2␣ inhibition promotes tumor cell death and, in contrast to HIF1␣, enhances the response to radiation treatment. Specifically, inhibiting HIF2␣ expression augments p53 activity, increases apoptosis, and reduces clonogenic survival of irradiated and non-irradiated cells. Moreover, HIF2␣ inhibition promotes p53-mediated responses by disrupting cellular redox homeostasis, thereby permitting reactive oxygen species (ROS) accumulation and DNA damage. These results correlate with altered p53 phosphorylation and target gene expression in untreated human tumor samples and show that HIF2␣ likely contributes to tumor cell survival including during radiation therapy.M any cellular responses to hypoxia are mediated by the hypoxia inducible factors (HIFs). These transcription factors promote the expression of over 200 genes (1) and are heterodimers consisting of either HIF1␣ or HIF2␣ bound to the HIF␤/ARNT subunit. While ARNT is constitutively expressed, both HIF␣ subunits are regulated by O 2 availability. Under normoxia, the von Hippel-Lindau (VHL) E3 ligase complex targets HIF␣ subunits for proteasomal degradation (2). When O 2 levels decline, the HIF␣ subunits are stabilized, bind ARNT, and activate the expression of target genes providing hypoxic adaptations.Solid tumors are characterized by oncogenic signaling and hypoxic microenvironments that promote HIF␣ accumulation (3). Moreover, HIF1␣ and/or HIF2␣ expression has been associated with increased tumor vascularization and poor prognosis of numerous cancers such as breast, ovarian, and non-small cell lung cancer (2, 4). Of note, in mouse xenograft models, HIF2␣ (and not HIF1␣) expression is crucial for growth of clear cell renal cell carcinoma (ccRCC) (5, 6) and neuroblastoma (7) tumors.TP53 is a tumor suppressor that is mutated or silenced in a majority of human cancers (8). It coordinates many cellular stress responses by regulating genes involved in DNA repair, cell cycle arrest, and apoptosis. Following stress stimuli, p53 is activated through a variety of post-translational modifications, including phosphorylation on serine 15 (9). For example, the ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2) kinases directly phosphorylate p53 in response to DNA damage, resulting in its activation (9). Although many tumors select for TP53 mutations, p53 pathway inhibition can also contribute to tumor progression (10).With the emergence of HIF inhibitors (11,12) and their potential use in cancer therapy, it is important to accurately predict the response of HIF␣-expressing tumor cells to treatment. HIF1␣ appears to enh...

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Peroxiredoxin III, a Mitochondrion-specific Peroxidase, Regulates Apoptotic Signaling by Mitochondria

Cited by 348 publications

References 84 publications

Radical-free biology of oxidative stress

Radical-free biology of oxidative stress

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses

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