{"title":"Ferritin with methylglyoxal produces reactive oxygen species but remains functional.","authors":"Adriana Rybnikářová, Richard Buchal, Jan Pláteník","doi":"10.1080/10715762.2024.2417281","DOIUrl":null,"url":null,"abstract":"<p><p>Iron is necessary for life, but the simultaneous iron-catalyzed formation of reactive oxygen species (ROS) is involved in pathogenesis of many diseases. One of them is diabetes mellitus, a widespread disease with severe long-term complications, including neuropathy, retinopathy, and nephropathy. Much evidence points to methylglyoxal, a potent glycating agent, as the key mediator of diabetic complications. In diabetes, there is also a peculiar dysregulation of iron homeostasis, leading to an expansion of redox-active iron. This <i>in vitro</i> study focuses on the interaction of methylglyoxal with ferritin, which is the main cellular protein for iron storage. Methylglyoxal effectively liberates iron from horse spleen ferritin, as well as synthetic iron cores; in both cases, it is partially mediated by superoxide. The interaction of methylglyoxal with ferritin increases the production of hydrogen peroxide, much above the generation of peroxide by methylglyoxal alone, in an iron-dependent manner. Glycation with methylglyoxal results in structural changes in ferritin. All of these findings can be demonstrated with pathophysiologically relevant (submillimolar) methylglyoxal concentrations. However, the rate of iron release by ascorbate, the ferroxidase activity, or the diameter of gated pores even in intensely glycated ferritin is not altered. In conclusion, although the functional features of ferritin resist alterations due to glycation, the interaction of methylglyoxal with ferritin liberates iron and markedly increases ROS production, both of which could enhance oxidative stress <i>in vivo</i>. Our findings may have implications for the pathogenesis of long-term diabetic complications, as well as for the use of ferritin as a nanocarrier in chemotherapy.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/10715762.2024.2417281","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Iron is necessary for life, but the simultaneous iron-catalyzed formation of reactive oxygen species (ROS) is involved in pathogenesis of many diseases. One of them is diabetes mellitus, a widespread disease with severe long-term complications, including neuropathy, retinopathy, and nephropathy. Much evidence points to methylglyoxal, a potent glycating agent, as the key mediator of diabetic complications. In diabetes, there is also a peculiar dysregulation of iron homeostasis, leading to an expansion of redox-active iron. This in vitro study focuses on the interaction of methylglyoxal with ferritin, which is the main cellular protein for iron storage. Methylglyoxal effectively liberates iron from horse spleen ferritin, as well as synthetic iron cores; in both cases, it is partially mediated by superoxide. The interaction of methylglyoxal with ferritin increases the production of hydrogen peroxide, much above the generation of peroxide by methylglyoxal alone, in an iron-dependent manner. Glycation with methylglyoxal results in structural changes in ferritin. All of these findings can be demonstrated with pathophysiologically relevant (submillimolar) methylglyoxal concentrations. However, the rate of iron release by ascorbate, the ferroxidase activity, or the diameter of gated pores even in intensely glycated ferritin is not altered. In conclusion, although the functional features of ferritin resist alterations due to glycation, the interaction of methylglyoxal with ferritin liberates iron and markedly increases ROS production, both of which could enhance oxidative stress in vivo. Our findings may have implications for the pathogenesis of long-term diabetic complications, as well as for the use of ferritin as a nanocarrier in chemotherapy.
期刊介绍:
Free Radical Research publishes high-quality research papers, hypotheses and reviews in free radicals and other reactive species in biological, clinical, environmental and other systems; redox signalling; antioxidants, including diet-derived antioxidants and other relevant aspects of human nutrition; and oxidative damage, mechanisms and measurement.