Dataset Information

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

ABSTRACT: The mitochondrial antioxidant manganese superoxide dismutase (MnSOD) is encoded by genomic DNA and its dismutase function is fully activated in the mitochondria to detoxify free radical O2(•-) generated by mitochondrial respiration. Accumulating evidence shows an extensive communication between the mitochondria and cytoplasm under oxidative stress. Not only is the MnSOD gene upregulated by oxidative stress, but MnSOD activity can be enhanced via the mitochondrial protein influx (MPI).A cluster of MPI containing cytoplasmic/nuclear proteins, such as cyclins, cyclin-dependent kinases, and p53 interact with and alter MnSOD activity. These proteins modulate MnSOD superoxide scavenging activity via post-translational modifications in the mitochondria. In addition to well-established pathways in gene expression, recent findings suggest that MnSOD enzymatic activity can also be enhanced by phosphorylation of specific motifs in mitochondria. This review attempts to discuss the pre- and post-translational regulation of MnSOD, and how these modifications alter MnSOD activity, which induces a cell adaptive response to oxidative stress.MnSOD is biologically significant to aerobic cells. Its role in protecting the cells against the deleterious effects of reactive oxygen species is evident. However, the exact network of MnSOD-associated cellular adaptive reaction to oxidative stress and its post-translational modifications, especially its enzymatic enhancement via phosphorylation, is not yet fully understood.The broad discussion of the multiple aspects of MnSOD regulation, including gene expression, protein modifications, and enzymatic activity, will shed light onto the unknown mechanisms that govern the prosurvival networks involved in cellular and mitochondrial adaptive response to genotoxic environment.

SUBMITTER: Candas D

PROVIDER: S-EPMC3942709 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

Candas Demet D Li Jian Jian JJ

Antioxidants & redox signaling 20130608 10

<h4>Significance</h4>The mitochondrial antioxidant manganese superoxide dismutase (MnSOD) is encoded by genomic DNA and its dismutase function is fully activated in the mitochondria to detoxify free radical O2(•-) generated by mitochondrial respiration. Accumulating evidence shows an extensive communication between the mitochondria and cytoplasm under oxidative stress. Not only is the MnSOD gene upregulated by oxidative stress, but MnSOD activity can be enhanced via the mitochondrial protein inf ...[more]

PMID: 23581847

Similar Datasets

Project description:BackgroundThe integrated stress response (ISR) is an evolutionarily conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery reperfusion, the most effective means to mitigate cardiac damage of myocardial infarction, causes additional reperfusion injury. This study aimed to investigate the role of the ISR in myocardial ischemia/reperfusion (I/R).MethodsCardiac-specific gain- and loss-of-function approaches for the ISR were used in vivo. Myocardial I/R was achieved by ligation of the cardiac left anterior descending artery for 45 minutes followed by reperfusion for different times. Cardiac function was assessed by echocardiography. Cultured H9c2 cells, primary rat cardiomyocytes, and mouse embryonic fibroblasts were used to dissect underlying molecular mechanisms. Tandem mass tag labeling and mass spectrometry was conducted to identify protein targets of the ISR. Pharmacologic means were tested to manipulate the ISR for therapeutic exploration.ResultsWe show that the PERK (PKR-like endoplasmic reticulum resident kinase)/eIF2α (α subunit of eukaryotic initiation factor 2) axis of the ISR is strongly induced by I/R in cardiomyocytes in vitro and in vivo. We further reveal a physiologic role of PERK/eIF2α signaling by showing that acute activation of PERK in the heart confers robust cardioprotection against reperfusion injury. In contrast, cardiac-specific deletion of PERK aggravates cardiac responses to reperfusion. Mechanistically, the ISR directly targets mitochondrial complexes through translational suppression. We identify NDUFAF2 (NADH:ubiquinone oxidoreductase complex assembly factor 2), an assembly factor of mitochondrial complex I, as a selective target of PERK. Overexpression of PERK suppresses the protein expression of NDUFAF2 and PERK inhibition causes an increase of NDUFAF2. Silencing of NDUFAF2 significantly rescues cardiac cell survival from PERK knockdown under I/R. We show that activation of PERK/eIF2α signaling reduces mitochondrial complex-derived reactive oxygen species and improves cardiac cell survival in response to I/R. Moreover, pharmacologic stimulation of the ISR protects the heart against reperfusion damage, even after the restoration of occluded coronary artery, highlighting clinical relevance for myocardial infarction treatment.ConclusionsThese results suggest that the ISR improves cell survival and mitigates reperfusion damage by selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in the heart.

Project description:BackgroundTo understand the molecular response of tumor cells to therapeutic ionizing radiation (IR), we previously reported that human breast cancer cells derived following chronic exposure to fractionated ionizing radiation (MCF+FIR) showed a transient radioresistance. MCF+FIR cells also demonstrated increased activity of NF-kappaB, increased expression of the mitochondrial antioxidant enzyme (MnSOD), and increased expression of a cell cycle regulatory protein (Cyclin B1). The present studies were designed to determine the relationship of NF-kappaB, MnSOD and Cyclin B1 expression in cellular adaptive responses to ionizing radiation.Materials and methodsThe first intron of the cyclin B1 gene with a putative NF-kappaB element was cloned into the pGL3 luciferase reporter (pGL3CB1EI1). PGL3CB1EI1 and control NF-kappaB luciferase activities were determined in MCF-7 and MCF+FIR cells treated with a single dose of radiation, over expression of the dominant negative mutant IkB (mIkB) or over expression of the SOD2 gene.ResultsMCF+FIR cells derived from fractionated IR demonstrated increased transactivation of the pGL3CB1EI1 and NF-kappaB controlled reporter activities, relative to the parental cell line. Transfection of dominant negative mutant IkB that inhibits NF-kappaB nuclear translocation, inhibited pGL3CB1EI1 and NF-kappaB activity, indicating the NF-kappaB dependence of pGL3CB1EI1 mediated transcription. In addition, over expression of the human SOD2 gene (MnSOD) inhibited NF-kappaB and pGL3CB1EI1 activity, indicating that superoxide or some species derived from superoxide may have participated in the up-regulation of reporter activity in response to chronic exposure to fractionated ionizing radiation. These results provide evidence suggesting that a signaling pathway involving NF-kappaB and Cyclin B1 may contribute to adaptive radioresistance induced by chronic exposure to fractionated IR and support the conclusion that MnSOD appears to be a negative regulator of this pathway.

Dataset Information

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

Publications

MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets