Transient mitochondrial transcript level decay in oxidative stressed chondrocytes

Vincent, F.; Corral‐Debrinski, Marisol; Adolphe, M

doi:10.1002/jcp.1041580116

Cited by 19 publications

(6 citation statements)

References 28 publications

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“…Our studies demonstrate that these findings extend to RLE and RPM cells and different forms of oxidative stress. In support of these findings, studies by others employing peroxisome proliferators or hypoxanthine-xanthine oxidase have revealed alterations in expression of ribosomal RNAs or NADH dehydrogenase (20,21). Importantly, in models of aging and diabetes that involve oxidative stress, both of these mitochondrial genes were affected as well (22,23).…”

Section: Discussionmentioning

confidence: 74%

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Modulation of mitochondrial gene expression in pulmonary epithelial cells exposed to oxidants.

Janssen

Driscoll

Timblin

et al. 1998

Environ Health Perspect

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Oxidants are important in the regulation of signal transduction and gene expression. Multiple classes of genes are transcriptionally activated by oxidants and are implicated in different phenotypic responses. In the present study, we performed differential mRNA display to elucidate genes that are induced or repressed after exposure of rat lung epithelial (RLE) cells to H2O2 or crocidolite asbestos, a pathogenic mineral that generates oxidants. After 8 or 24 hr of exposure, RNA was extracted, reverse transcribed, and amplified by polymerase chain reaction with degenerate primers to visualize alterations in gene expression. The seven clones obtained were sequenced and encoded the mitochondrial genes, NADH dehydrogenase subunits ND5 and ND6, and 16S ribosomal RNA. Evaluation of their expression by Northern blot analysis revealed increased expression of 16S rRNA after 1 or 2 hr of exposure to H2O2. At later time periods (4 and 24 hr), mRNA levels of 16S rRNA and NADH dehydrogenase were decreased in H2O2-treated RLE cells when compared to sham controls. Crocidolite asbestos caused increases in 16S rRNA levels after 8 hr of exposure, whereas after 24 hr of exposure to asbestos, 16S rRNA levels were decreased in comparison to sham controls. In addition to these oxidants, the nitric oxide generator spermine NONOate caused similar decreases in NADH dehydrogenase mRNA levels after 4 hr of exposure. The present data and previous studies demonstrated that all oxidants examined resulted in apoptosis in RLE cells during the time frame where alterations of mitochondrial gene expression were observed. As the mitochondrion is a major organelle that controls apoptosis, alterations in expression of mitochondrial genes may be involved in the regulation of apoptosis.ImagesFigure 1Figure 2Figure 3Figure 4Figure 5

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Section: Discussionmentioning

confidence: 74%

“…Importantly, in models of aging and diabetes that involve oxidative stress, both of these mitochondrial genes were affected as well (22,23). The increases and decreases in RNAs observed in these models may reflect the type or duration of oxidative stress encountered (20,21).…”

Section: Discussionmentioning

confidence: 96%

Modulation of mitochondrial gene expression in pulmonary epithelial cells exposed to oxidants.

Janssen

Driscoll

Timblin

et al. 1998

Environ Health Perspect

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“…As an acute response, the formation of stress granules temporarily represses global translation and also preserves mRNA (18). It is not uncommon for cells to employ additional mechanisms such as the cleavage of tRNA (39) and/or decrease in rRNA (40) to ensure translational repression. Along this line of reasoning, in AD, it is possible that reduced rRNA levels may represent an adaptive response in addition to the GVD/stress granule formation to ensure translation repression during the chronic stress neurons are facing and that those neurons with such successful adaptations have a larger chance to survive.…”

Section: Discussionmentioning

confidence: 99%

A novel origin for granulovacuolar degeneration in aging and Alzheimer's disease: parallels to stress granules

Castellani

Gupta

Sheng

et al. 2011

Laboratory Investigation

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The phosphorylated ribosomal protein S6 (pS6) is associated with the 40S ribosomal subunit in eukaryotes and is thought to play a role in RNA storage, degradation, and re-entry into translation. In this study, we found pS6 localized to granulovacuolar degeneration (GVD) within pyramidal neurons. Immunohistochemical analysis found nearly 20 fold more neurons contain pS6 positive granules in Alzheimer’s disease (AD) hippocampus compared with age-matched controls. Further, pS6-positive granules were more common in neurons not containing neurofibrillary tangles, were never associated with extracellular neurofibrillary tangles or in apoptotic neurons, and contained less RNA than neighboring pyramidal neurons not containing pS6-positive granules. In model systems, pS6 is a specific marker for stress granules, and another stress granule protein, p54/Rck we also found to be a component of GVD in the current study. Stress granules are transient, intracellular, dense aggregations of proteins and RNAs that accumulate as a stress response, protecting cells from apoptosis and inappropriate transcriptional activity, often described as a form of “molecular triage.” The RNA oxidation modification 8-hydroxyguanosine (8OHG) is strikingly increased in AD, yet this study reports that those neurons with pS6 granules display reduced RNA oxidation demonstrated by lower levels of 8OHG. Since chronic oxidative stress is central to AD pathogenesis, and RNA is a specific oxidative stress target and is intimately associated with stress granule biogenesis in model systems, we suggest that GVD in human brain parallel stress granules, and may in fact be more representative of early disease pathogenesis than traditionally believed. This proposed origin for GVD as a neuroprotective response, may represent a morphologic checkpoint between cell death and reversible cellular stress that proceeds in the absence of other inclusions.

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“…Mitochondria also represent a potential source of injury‐related ROS in cartilage. Increased free radical production is associated with direct oxidative damage to mitochondrial electron transport complexes or to the DNA that encodes them 5, 28, 29. Excessive free radical production is characteristic of chondrocytes in osteoarthritic cartilage, which are also deficient in respiratory activity 28, 30.…”

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confidence: 99%

Rotenone prevents impact‐induced chondrocyte death

Goodwin

McCabe

Sauter

et al. 2010

Journal Orthopaedic Research

122

137

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Mechanical insult to articular cartilage kills chondrocytes, an event that may increase the risk of post-traumatic osteoarthritis. Recent reports indicate that antioxidants decrease impact induced chondrocyte death, but the source(s) of oxidants, the time course of oxidant release, and the identity of the oxidative species generated in response to injury are unknown. A better understanding of these processes could lead to new treatments of acute joint injuries. To that end we studied the kinetics and distribution of oxidant production in osteochondral explants subjected to a single blunt impact injury. We followed superoxide production by measuring the time-dependent accumulation of chondrocyte nuclei stained with the superoxide-sensitive probe dihydroethidium. The percentage of chondrocytes that were dihydroethidium-positive was 35% above baseline 10 minutes after impact and 65% above baseline 60 minutes after impact. Most positive cells were found within and near areas contacted directly by the impact platen. Rotenone, an electron transport chain inhibitor, was used to test the hypothesis that mitochondria contribute to superoxide release. Rotenone treatment significantly reduced dihydroethidium staining, which remained steady at 15% above baseline for up to 60 minutes post-impact. Moreover, rotenone reduced chondrocyte death in impact sites by more than 40% even when administered two hours after injury (p < 0.001). These data show that much of the acute chondrocyte mortality caused by in vitro impact injuries results from superoxide release from mitochondria and suggest that brief exposure to free radical scavengers could significantly improve chondrocyte viability following joint injury.

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Transient mitochondrial transcript level decay in oxidative stressed chondrocytes

Cited by 19 publications

References 28 publications

Modulation of mitochondrial gene expression in pulmonary epithelial cells exposed to oxidants.

Modulation of mitochondrial gene expression in pulmonary epithelial cells exposed to oxidants.

A novel origin for granulovacuolar degeneration in aging and Alzheimer's disease: parallels to stress granules

Rotenone prevents impact‐induced chondrocyte death

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