Superoxide Mediates Acute Liver Injury in Irradiated Mice Lacking Sirtuin 3

Coleman, Mitchell C.; Olivier, Alicia K.; Jacobus, James A.; Mapuskar, Kranti A.; Mao, Gaowei; Martin, Sebastian; Riley, Dennis P.; Gius, David; Spitz, Douglas R.

doi:10.1089/ars.2012.5091

Cited by 33 publications

(44 citation statements)

References 43 publications

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“…FoxOs also engage in crosstalk with the sirtuin family proteins. For example, sirtuin 3 (SIRT3), a protein deacetylase, is an important regulator of mitochondrial oxidative metabolism after exposure to radiation and other oxidative stresses both in vitro and in vivo (146). It abrogates mitochondrial • O 2 − production by regulating SOD2 expression transcriptionally through FoxO3a as well as via deacetylation of SOD2 at lysine residues, which results in increased SOD2 activity (146).…”

Section: Discussionmentioning

confidence: 99%

“…For example, sirtuin 3 (SIRT3), a protein deacetylase, is an important regulator of mitochondrial oxidative metabolism after exposure to radiation and other oxidative stresses both in vitro and in vivo (146). It abrogates mitochondrial • O 2 − production by regulating SOD2 expression transcriptionally through FoxO3a as well as via deacetylation of SOD2 at lysine residues, which results in increased SOD2 activity (146). These events also appear to crosstalk with p53 signaling insofar as SIRT3 may further promote cell survival after irradiation/oxidative stress by deacetylating the pool of p53 that translocates to the mitochondria in response to increased • O 2 − generation, thereby enhancing p53 degradation (146).…”

Section: Discussionmentioning

confidence: 99%

“…It abrogates mitochondrial • O 2 − production by regulating SOD2 expression transcriptionally through FoxO3a as well as via deacetylation of SOD2 at lysine residues, which results in increased SOD2 activity (146). These events also appear to crosstalk with p53 signaling insofar as SIRT3 may further promote cell survival after irradiation/oxidative stress by deacetylating the pool of p53 that translocates to the mitochondria in response to increased • O 2 − generation, thereby enhancing p53 degradation (146). That a failure of cells to regulate • O 2 − can have major in vivo functional consequences is clearly illustrated by its direct association with functional liver injury in irradiated SIRT3-knockout mice (146).…”

Section: Discussionmentioning

confidence: 99%

“…These events also appear to crosstalk with p53 signaling insofar as SIRT3 may further promote cell survival after irradiation/oxidative stress by deacetylating the pool of p53 that translocates to the mitochondria in response to increased • O 2 − generation, thereby enhancing p53 degradation (146). That a failure of cells to regulate • O 2 − can have major in vivo functional consequences is clearly illustrated by its direct association with functional liver injury in irradiated SIRT3-knockout mice (146). In another intriguing study, donor age-related changes in mitochondrial oxidative metabolism leading to • O 2 − accumulation in human fibroblasts were associated with increased sensitivity to radiation and chemotherapy (147).…”

Section: Discussionmentioning

confidence: 99%

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Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

2018

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There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular “DNA-damage response”, including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early-versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

2018

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“…Regarding the IR conditions, the excessive generation of O 2 •− molecules caused mitochondrial dysfunction that contributes to liver injury [40]. Our study showed that the correlation between depletion of SOD activities and enhancement of apoptosis signals was due to radiation (Fig.…”

Section: Discussionmentioning

confidence: 66%

Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis

Kim

Jang

Lee

et al. 2017

Journal of Ginseng Research

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BackgroundRadiotherapy is one of the most important modalities in cancer treatment; however, normal tissue damage is a serious concern. Drug development for the protection or reduction of normal tissue damage is therefore a clinical issue. Herein, we evaluated the protective properties of Panax ginseng Meyer and its corresponding mechanisms.MethodsC56BL/6 mice were orally pretreated with P. ginseng water extract (PGE; 25 mg/kg, 50 mg/kg, or 100 mg/kg) or intraperitoneally injected melatonin (20 mg/kg) for 4 d consecutively, then exposed to 15-Gy X-ray radiation 1 h after the last administration. After 10 d of irradiation, the biological properties of hematoxicity, fat accumulation, histopathology, oxidative stress, antioxidant activity, pro-inflammatory cytokines, and apoptosis signals were examined in the hepatic tissue.ResultsThe irradiation markedly induced myelosuppression as determined by hematological analysis of the peripheral blood. Steatohepatitis was induced by X-ray irradiations, whereas pretreatment with PGE significantly attenuated it. Oxidative stress was drastically increased, whereas antioxidant components were depleted by irradiation. Irradiation also notably increased serum liver enzymes and hepatic protein levels of pro-inflammatory cytokines. Those alterations were markedly normalized by pretreatment with PGE. The degree of irradiation-induced hepatic tissue apoptosis was also attenuated by pretreatment with PGE, which was evidenced by a terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick-end labeling assay, western blotting, and gene expressions analysis, particularly of apoptotic molecules.ConclusionWe suggest that PGE could be applicable for use against radiation-induced liver injury, and its corresponding mechanisms involve the modulation of oxidative stress, inflammatory reactions, and apoptosis.

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Using mitochondrial sirtuins as drug targets: disease implications and available compounds

Gertz

Steegborn

2016

Cell. Mol. Life Sci.

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Sirtuins are an evolutionary conserved family of NAD(+)-dependent protein lysine deacylases. Mammals have seven Sirtuin isoforms, Sirt1-7. They contribute to regulation of metabolism, stress responses, and aging processes, and are considered therapeutic targets for metabolic and aging-related diseases. While initial studies were focused on Sirt1 and 2, recent progress on the mitochondrial Sirtuins Sirt3, 4, and 5 has stimulated research and drug development for these isoforms. Here we review the roles of Sirtuins in regulating mitochondrial functions, with a focus on the mitochondrially located isoforms, and on their contributions to disease pathologies. We further summarize the compounds available for modulating the activity of these Sirtuins, again with a focus on mitochondrial isoforms, and we describe recent results important for the further improvement of compounds. This overview illustrates the potential of mitochondrial Sirtuins as drug targets and summarizes the status, progress, and challenges in developing small molecule compounds modulating their activity.

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Superoxide Mediates Acute Liver Injury in Irradiated Mice Lacking Sirtuin 3

Cited by 33 publications

References 43 publications

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis

Using mitochondrial sirtuins as drug targets: disease implications and available compounds

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