Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu srovnávací studie, časopisecké články, práce podpořená grantem
PubMed
25482261
DOI
10.1016/j.bbabio.2014.12.002
PII: S0005-2728(14)00660-4
Knihovny.cz E-zdroje
- Klíčová slova
- Bioenergetics, Cell death, Glycolytic flux, Mitochondrial dysfunction, Oxidative stress, Polyethylenimine,
- MeSH
- adenosintrifosfát metabolismus MeSH
- antioxidancia metabolismus farmakologie MeSH
- buněčná membrána účinky léků metabolismus MeSH
- buněčné dýchání účinky léků MeSH
- buněčné linie MeSH
- energetický metabolismus účinky léků MeSH
- glutathion metabolismus MeSH
- homeostáza MeSH
- kinetika MeSH
- lidé MeSH
- mitochondriální membrány účinky léků metabolismus MeSH
- molekulární struktura MeSH
- molekulová hmotnost MeSH
- oxidace-redukce MeSH
- oxidační stres účinky léků MeSH
- polyethylenimin chemie toxicita MeSH
- reaktivní formy kyslíku metabolismus MeSH
- spotřeba kyslíku účinky léků MeSH
- transfekce metody MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- adenosintrifosfát MeSH
- antioxidancia MeSH
- glutathion MeSH
- polyethylenimin MeSH
- reaktivní formy kyslíku 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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