Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

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Abstract

The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

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Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

Konstantinos Palikaras, Eirini Lionaki, Nektarios Tavernarakis (2015)

Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.

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A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62.

Alexandria Lau, Xiao-Jun Wang, Fei Zhao … (2010)

In response to stress, cells can utilize several cellular processes, such as autophagy, which is a bulk-lysosomal degradation pathway, to mitigate damages and increase the chances of cell survival. Deregulation of autophagy causes upregulation of p62 and the formation of p62-containing aggregates, which are associated with neurodegenerative diseases and cancer. The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling the expression of many cellular protective proteins. Under basal conditions, Nrf2 is ubiquitinated by the Keap1-Cul3-E3 ubiquitin ligase complex and targeted to the 26S proteasome for degradation. Upon induction, the activity of the E3 ubiquitin ligase is inhibited through the modification of cysteine residues in Keap1, resulting in the stabilization and activation of Nrf2. In this current study, we identified the direct interaction between p62 and Keap1 and the residues required for the interaction have been mapped to 349-DPSTGE-354 in p62 and three arginines in the Kelch domain of Keap1. Accumulation of endogenous p62 or ectopic expression of p62 sequesters Keap1 into aggregates, resulting in the inhibition of Keap1-mediated Nrf2 ubiquitination and its subsequent degradation by the proteasome. In contrast, overexpression of mutated p62, which loses its ability to interact with Keap1, had no effect on Nrf2 stability, demonstrating that p62-mediated Nrf2 upregulation is Keap1 dependent. These findings demonstrate that autophagy deficiency activates the Nrf2 pathway in a noncanonical cysteine-independent mechanism.

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A single p450 allele associated with insecticide resistance in Drosophila.

P J Daborn, J. L. Yen, M R Bogwitz … (2002)

Insecticide resistance is one of the most widespread genetic changes caused by human activity, but we still understand little about the origins and spread of resistant alleles in global populations of insects. Here, via microarray analysis of all P450s in Drosophila melanogaster, we show that DDT-R, a gene conferring resistance to DDT, is associated with overtranscription of a single cytochrome P450 gene, Cyp6g1. Transgenic analysis of Cyp6g1 shows that overtranscription of this gene alone is both necessary and sufficient for resistance. Resistance and up-regulation in Drosophila populations are associated with a single Cyp6g1 allele that has spread globally. This allele is characterized by the insertion of an Accord transposable element into the 5' end of the Cyp6g1 gene.

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Author and article information

Contributors

Agnieszka Loboda: +48-12-664-64-12 , agnieszka.loboda@uj.edu.pl

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell. Mol. Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 21 April 2016

Publication date PMC-release: 21 April 2016

Publication date (Print): 2016

Volume: 73

Pages: 3221-3247

Affiliations

[1 ]Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland

[2 ]Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland

[3 ]Department of Cell Biology and Imaging, Faculty of Biology and Earth Sciences, Jagiellonian University, Krakow, Poland

Article

Publisher ID: 2223

DOI: 10.1007/s00018-016-2223-0

PMC ID: 4967105

PubMed ID: 27100828

SO-VID: df8aca00-381e-42ea-bd35-d392a1c9672c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 27 January 2016

Date revision received : 7 April 2016

Date accepted : 8 April 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;

Award ID: 2012/07/B/NZ3/02908

Award ID: 2012/07/B/NZ1/02881

Award ID: 2012/06/A/NZ1/0004

Award ID: 2014/14/M/NZ1/00010

Award ID: 2012/06/M/NZ1/00008

Award Recipient : Elzbieta Pyza Alicja Jozkowicz Jozef Dulak

Funded by: FundRef http://dx.doi.org/10.13039/501100005632, Narodowe Centrum Badań i Rozwoju;

Award ID: PBS2/B7/15/2014

Custom metadata

ScienceOpen disciplines: Molecular biology

Keywords: heme oxygenase-1 (ho-1),kelch-like ech-associated protein 1 (keap1),nuclear factor erythroid 2-related factor 2 (nrf2),oxidative stress,reactive oxygen species (ros)

Data availability:

ScienceOpen disciplines: Molecular biology

Keywords: heme oxygenase-1 (ho-1), kelch-like ech-associated protein 1 (keap1), nuclear factor erythroid 2-related factor 2 (nrf2), oxidative stress, reactive oxygen species (ros)

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

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Abstract

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Stress signalling in stem cells

Most cited references 176

Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62.

A single p450 allele associated with insecticide resistance in Drosophila.

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