ArticleThe Journal of biological chemistry2012
Oxidative stress induced S-glutathionylation and proteolytic degradation of mitochondrial thymidine kinase 2.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
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- Biological sex impacts oxidative stress in skeletal muscle in a porcine heat stress model.American journal of physiology. Regulatory, integrative and comparative physiology · 2024Article
- Gbb glutathionylation promotes its proteasome-mediated degradation to inhibit synapse growth.The Journal of cell biology · 2023Article
- Mitochondria Need Their Sleep: Redox, Bioenergetics, and Temperature Regulation of Circadian Rhythms and the Role of Cysteine-Mediated Redox Signaling, Uncoupling Proteins, and Substrate Cycles.Antioxidants (Basel, Switzerland) · 2023Article
- Glutathionylation Decreases Methyltransferase Activity of PRMT5 and Inhibits Cell Proliferation.Molecular & cellular proteomics : MCP · 2020Article
- Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency.BMC molecular and cell biology · 2020Article
- Electrophiles Against (Skin) Diseases: More Than Nrf2.Biomolecules · 2020Review
- Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations.Antioxidants (Basel, Switzerland) · 2020Review
- Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis.Nature communications · 2019Article
- KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to EnhancedAntioxidants (Basel, Switzerland) · 2019Article
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- Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells.Redox biology · 2018Article
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- Evaluation of Lymphocyte Response to the Induced Oxidative Stress in a Cohort of Ageing Subjects, including Semisupercentenarians and Their Offspring.Mediators of inflammation · 2018Article
- Structural Basis for Redox Regulation of Cytoplasmic and Chloroplastic Triosephosphate Isomerases fromFrontiers in plant science · 2016Article
- Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications.Physiological reviews · 2016Review
- Biological chemistry and functionality of protein sulfenic acids and related thiol modifications.Free radical research · 2016Review
- Zidovudine induces downregulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs.Antimicrobial agents and chemotherapy · 2014Article
- Pleiotropic functions of glutathione S-transferase P.Advances in cancer research · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein glutathionylation in response to oxidative stress can affect both the stability and activity of target proteins. Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in mitochondrial DNA precursor synthesis. Using an antibody specific for glutathione (GSH), S-glutathionylated TK2 was detected after the addition of glutathione disulfide (GSSG) but not GSH. This was reversed by the addition of dithiothreitol, suggesting that S-glutathionylation of TK2 is reversible. Site-directed mutagenesis of the cysteine residues and subsequent analysis of mutant enzymes demonstrated that Cys-189 and Cys-264 were specifically glutathionylated by GSSG. These cysteine residues do not appear to be part of the active site, as demonstrated by kinetic studies of the mutant enzymes. Treatment of isolated rat mitochondria with hydrogen peroxide resulted in S-glutathionylation of added recombinant TK2. Treatment of intact cells with hydrogen peroxide led to reduction of mitochondrial TK2 activity and protein levels, as well as S-glutathionylation of TK2. Furthermore, the addition of S-glutathionylated recombinant TK2 to mitochondria isolated from hydrogen peroxide-treated cells led to degradation of the S-glutathionylated TK2, which was not observed with unmodified TK2. S-Glutathionylation on Cys-189 was responsible for the observed selective degradation of TK2 in mitochondria. These results strongly suggest that oxidative damage-induced S-glutathionylation and degradation of TK2 have significant impact on mitochondrial DNA precursor synthesis.
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