Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis
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Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis. / Hall, Arnaldur; Parhamifar, Ladan; Lange, Marina Krarup; Meyle, Kathrine Damm; Sanderhoff, May; Andersen, Helene; Roursgaard, Martin; Larsen, Anna Karina; Jensen, Per Bo; Christensen, Claus; Bartek, Jiri; Moghimi, Seyed Moein.
In: B B A - Bioenergetics, Vol. 1847, No. 3, 03.2015, p. 328-42.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis
AU - Hall, Arnaldur
AU - Parhamifar, Ladan
AU - Lange, Marina Krarup
AU - Meyle, Kathrine Damm
AU - Sanderhoff, May
AU - Andersen, Helene
AU - Roursgaard, Martin
AU - Larsen, Anna Karina
AU - Jensen, Per Bo
AU - Christensen, Claus
AU - Bartek, Jiri
AU - Moghimi, Seyed Moein
N1 - Copyright © 2014 Elsevier B.V. All rights reserved.
PY - 2015/3
Y1 - 2015/3
N2 - 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.
AB - 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.
KW - Adenosine Triphosphate
KW - Antioxidants
KW - Cell Line
KW - Cell Membrane
KW - Cell Respiration
KW - Cell Survival
KW - Dose-Response Relationship, Drug
KW - Energy Metabolism
KW - Glutathione
KW - Homeostasis
KW - Humans
KW - Kinetics
KW - Mitochondrial Membranes
KW - Molecular Structure
KW - Molecular Weight
KW - Oxidation-Reduction
KW - Oxidative Stress
KW - Oxygen Consumption
KW - Polyethyleneimine
KW - Reactive Oxygen Species
KW - Structure-Activity Relationship
KW - Transfection
U2 - 10.1016/j.bbabio.2014.12.002
DO - 10.1016/j.bbabio.2014.12.002
M3 - Journal article
C2 - 25482261
VL - 1847
SP - 328
EP - 342
JO - B B A - Bioenergetics
JF - B B A - Bioenergetics
SN - 0005-2728
IS - 3
ER -
ID: 161441359