Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis
Language English Country Netherlands Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
25482261
DOI
10.1016/j.bbabio.2014.12.002
PII: S0005-2728(14)00660-4
Knihovny.cz E-resources
- Keywords
- Bioenergetics, Cell death, Glycolytic flux, Mitochondrial dysfunction, Oxidative stress, Polyethylenimine,
- MeSH
- Adenosine Triphosphate metabolism MeSH
- Antioxidants metabolism pharmacology MeSH
- Cell Membrane drug effects metabolism MeSH
- Cell Respiration drug effects MeSH
- Cell Line MeSH
- Energy Metabolism drug effects MeSH
- Glutathione metabolism MeSH
- Homeostasis MeSH
- Kinetics MeSH
- Humans MeSH
- Mitochondrial Membranes drug effects metabolism MeSH
- Molecular Structure MeSH
- Molecular Weight MeSH
- Oxidation-Reduction MeSH
- Oxidative Stress drug effects MeSH
- Polyethyleneimine chemistry toxicity MeSH
- Reactive Oxygen Species metabolism MeSH
- Oxygen Consumption drug effects MeSH
- Transfection methods MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Adenosine Triphosphate MeSH
- Antioxidants MeSH
- Glutathione MeSH
- Polyethyleneimine MeSH
- Reactive Oxygen Species MeSH
Polyethylenimines (PEIs) are among the most efficient polycationic non-viral transfectants. PEI architecture and size not only modulate transfection efficiency, but also cytotoxicity. However, the underlying mechanisms of PEI-induced multifaceted cell damage and death are largely unknown. Here, we demonstrate that the central mechanisms of PEI architecture- and size-dependent perturbations of integrated cellular metabolomics involve destabilization of plasma membrane and mitochondrial membranes with consequences on mitochondrial oxidative phosphorylation (OXPHOS), glycolytic flux and redox homeostasis that ultimately modulate cell death. In comparison to linear PEI, the branched architectures induced greater plasma membrane destabilization and were more detrimental to glycolytic activity and OXPHOS capacity as well as being a more potent inhibitor of the cytochrome c oxidase. Accordingly, the branched architectures caused a greater lactate dehydrogenase (LDH) and ATP depletion, activated AMP kinase (AMPK) and disturbed redox homeostasis through diminished availability of nicotinamide adenine dinucleotide phosphate (NADPH), reduced antioxidant capacity of glutathione (GSH) and increased burden of reactive oxygen species (ROS). The differences in metabolic and redox imprints were further reflected in the transfection performance of the polycations, but co-treatment with the GSH precursor N-acetyl-cysteine (NAC) counteracted redox dysregulation and increased the number of viable transfected cells. Integrated biomembrane integrity and metabolomic analysis provides a rapid approach for mechanistic understanding of multifactorial polycation-mediated cytotoxicity, and could form the basis for combinatorial throughput platforms for improved design and selection of safer polymeric vectors.
Genome Integrity Unit Danish Cancer Society Research Center Copenhagen Denmark
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