Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Autoren

Debapriya Chakraborty
Vanessa Felzen
Christof Hiebel
Elisabeth Stürner
Natarajan Perumal
Caroline Manicam
Elisabeth Sehn
Franz Grus
Uwe Wolfrum
Christian Behl

DOI

10.1016/j.redox.2019.101181

ISSN

2213-2317

Zeitschrift

Redox Biology

Sprache

en

Artikelnummer

101181

Paginierung

101181 - 101181

Datum der Veröffentlichung

2019

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.redox.2019.101181

Datum der Datenerfassung

2019

Titel

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Ausgabe der Zeitschrift

24

Datenquelle: Crossref

Abstract

Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells, was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over an important part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.

Addresses

Institute of Pathobiochemistry, University Medical Center Mainz of the Johannes Gutenberg University, 55099, Mainz, Germany. Electronic address: debapriya222@gmail.com.

Autoren

Debapriya Chakraborty
Vanessa Felzen
Christof Hiebel
Elisabeth Stürner
Natarajan Perumal
Caroline Manicam
Elisabeth Sehn
Franz Grus
Uwe Wolfrum
Christian Behl

DOI

10.1016/j.redox.2019.101181

eISSN

2213-2317

Externe Identifier

PubMed Identifier: 30959460
PubMed Central ID: PMC6454062

Funding acknowledgements

Deutsche Forschungsgemeinschaft: CRC1177
DFG: MA 8006/1-1
Foundation Fighting Blindness: PPA-0717-0719-RAD
Peter Beate Heller Foundation:

Open access

true

ISSN

2213-2317

Zeitschrift

Redox biology

Schlüsselwörter

Neurons
Cell Line
Lysosomes
Mitochondria
Humans
Proteasome Endopeptidase Complex
Adaptor Proteins, Signal Transducing
Oxidative Stress
Phosphorylation
Models, Biological
Autophagy
Apoptosis Regulatory Proteins
TOR Serine-Threonine Kinases
Autophagosomes
Macroautophagy

Sprache

eng

Medium

Print-Electronic

Online publication date

2019

Open access status

Open Access

Paginierung

101181

Datum der Veröffentlichung

2019

Status

Published

Publisher licence

CC BY-NC-ND

Datum der Datenerfassung

2019

Titel

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

24

Files

https://europepmc.org/articles/PMC6454062?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells, was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over an important part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.

Date of acceptance

2019

Autoren

Debapriya Chakraborty
Vanessa Felzen
Christof Hiebel
Elisabeth Stürner
Natarajan Perumal
Caroline Manicam
Elisabeth Sehn
Franz Grus
Uwe Wolfrum
Christian Behl

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/30959460

DOI

10.1016/j.redox.2019.101181

eISSN

2213-2317

Externe Identifier

PubMed Central ID: PMC6454062

Zeitschrift

Redox Biol

Schlüsselwörter

Adaptation
Autophagy
BAG3
Oxidative stress
Protein homeostasis
Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
Autophagosomes
Autophagy
Cell Line
Humans
Lysosomes
Macroautophagy
Mitochondria
Models, Biological
Neurons
Oxidative Stress
Phosphorylation
Proteasome Endopeptidase Complex
TOR Serine-Threonine Kinases

Sprache

eng

Country

Netherlands

Paginierung

101181

PII

S2213-2317(19)30047-3

Datum der Veröffentlichung

2019

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2020

Titel

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

24

Datenquelle: PubMed

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Files

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