Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis

Arnaldur Hall; Ladan Parhamifar; Marina Krarup Lange; Kathrine Damm Meyle; May Sanderhoff; Helene Andersen; Martin Roursgaard; Anna Karina Larsen; Per Bo Jensen; Claus Christensen; Jiri Bartek; Seyed Moein Moghimi

doi:10.1016/j.bbabio.2014.12.002

Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis

Arnaldur Hall, Ladan Parhamifar, Marina Krarup Lange, Kathrine Damm Meyle, May Sanderhoff, Helene Andersen, Martin Roursgaard, Anna Karina Larsen, Per Bo Jensen, Claus Christensen, Jiri Bartek, Seyed Moein Moghimi

26 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	B B A - Bioenergetics
Vol/bind	1847
Udgave nummer	3
Sider (fra-til)	328-42
Antal sider	15
ISSN	0005-2728
DOI	https://doi.org/10.1016/j.bbabio.2014.12.002
Status	Udgivet - mar. 2015

Adgang til dokumentet

10.1016/j.bbabio.2014.12.002

Citationsformater

Hall, A., Parhamifar, L., Lange, M. K., Meyle, K. D., Sanderhoff, M., Andersen, H., Roursgaard, M., Larsen, A. K., Jensen, P. B., Christensen, C., Bartek, J., & Moghimi, S. M. (2015). Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis. B B A - Bioenergetics, 1847(3), 328-42. https://doi.org/10.1016/j.bbabio.2014.12.002

@article{136043170b6a4e98b07859d8271cc286,

title = "Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis",

abstract = "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.",

keywords = "Adenosine Triphosphate, Antioxidants, Cell Line, Cell Membrane, Cell Respiration, Cell Survival, Dose-Response Relationship, Drug, Energy Metabolism, Glutathione, Homeostasis, Humans, Kinetics, Mitochondrial Membranes, Molecular Structure, Molecular Weight, Oxidation-Reduction, Oxidative Stress, Oxygen Consumption, Polyethyleneimine, Reactive Oxygen Species, Structure-Activity Relationship, Transfection",

author = "Arnaldur Hall and Ladan Parhamifar and Lange, {Marina Krarup} and Meyle, {Kathrine Damm} and May Sanderhoff and Helene Andersen and Martin Roursgaard and Larsen, {Anna Karina} and Jensen, {Per Bo} and Claus Christensen and Jiri Bartek and Moghimi, {Seyed Moein}",

year = "2015",

month = mar,

doi = "10.1016/j.bbabio.2014.12.002",

language = "English",

volume = "1847",

pages = "328--42",

journal = "B B A - Bioenergetics",

issn = "0005-2728",

publisher = "Elsevier",

number = "3",

}

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

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

SN - 0005-2728

VL - 1847

SP - 328

EP - 342

JO - B B A - Bioenergetics

JF - B B A - Bioenergetics

IS - 3

ER -

Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater