Lipidiperoksidaatio, FERROPTOOSI ja NRF2

 https://www.ncbi.nlm.nih.gov/pubmed/30042655  

2018

FERROPTOOSI on äskettäin kuvattu uusi säädetyn solukuoleman muoto, joka on eri kuin apoptoosi, nekroptoosi tai muut solukuoleman muodot.  Ferroptoosia indusoi  Glutationisynteesin keskeytyminen tai glutationiperoksidasi4:n estyminen ;   rauta lisää ferroptoosia ; ferroptoosia estää  vapaita radikaaleja pyystävät aineet  kuten ferrostatiini-1, liprostatiini-1 ja endogeeninen E-vitamiini.

Ferroptoosi  terminoituu mitokondriaalisen  dysfunktioon  ja toksiseen lipidiperoksidaatioon. Vaikka onkin haastavaa tunnistaa elävästä kehosta  ferroptoosia , monet neurodegeneraatioiden  hyvin  selvitetyt piirteet  ovat  myös johdonmukaisesti   esiintyviä ferroptoosissa, kuten  lipidiperoksidaatio, mitokondriaalinen  rikkoutuminen ja raudan vikasäätyminen. Niinpä neurodegeneraatiossa esiintyvän ferroptoosin osuus  on alkanut kiinnostaa enemmän ja spesifistä näyttöäkin  kertyy nopeaan. 

Eräs näkökohta, jota on  niukasti  huomioitu aiemmin  on NRF2,  antioksidanttien transkriptiofaktori, tumafaktori erytoidi-2:n kaltainen tekijä 2.  Tämä transkriptiofaktori säätelee satoja geenejä, joista usea on joko suoraan tai epåäsuoraan osallistumassa ferroptoosin modulointiin,   sisällyttäen tähän GSH:n, raudan ja lipidien aineenvaihdunnan sekä mitokondrianfunktio. 

Tämä  mahdollisesti asettaa NRF2:n determinoivaksi avainkomponentiksi  sen   moduloidessa ferroptoottisen stressin  alkua ja tuloksia.   Minimaalinen suora näyttö  jota nkyään on saatavilla,  on saatujen tietojen kanssa konsistenttia. Nrf2 saattaa olla kriittisen tärkeä  suojauduttaessa  ferroptoosilta.  Ja päinvastoin sellainen näyttö on erittäin runsasta, että Nrf2 - signaloinnin lisääntyminen on vahvasti neuroprotektiivista  neurodegeneraatiomalleissa, vaikka onkin epäselvää , mikä on se  eksakti mekanismi , jolla sellaisa tuloksia saadaan.  

Lisätutkimuksia tarvitaan   vahvistamaan, missä määrin Nrf2:n neuroprotektiivinen aktivaatio  osallistuu ferroptoosin estoon.

Abstract

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging.
 One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function.
This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress.
The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear.
Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis.

KEYWORDS:

Alzheimer’s disease; Huntington’s disease; Keap1; Parkinson’s disease; RSL3; erastin; motor neuron disease; system xc-

PMID:

30042655

PMCID:

PMC6048292

DOI:

10.3389/fnins.2018.00466

Free PMC Article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048292/bin/fnins-12-00466-g001.jpg

( KUVA, joka liittyy artikkeliin): 

Ferroptosis and its molecular regulation by Nrf2. 

Glutathione peroxidase 4 (Gpx4) utilizes the major cellular antioxidant glutathione (GSH) as a substrate to reduce lipid hydroperoxides (LOOH).

 Oxidized glutathione (GSSG) generated by Gpx4 is reduced back to glutathione (GSH) by glutathione reductase (GR) in a reaction requiring NADPH, 

which can be regenerated by glucose-6-phosphate dehydrogenase (G6PD) and phosphogluconate dehydrogenase (PGD) of the pentose-phosphate pathway, and malic enzyme (ME). 

The tripeptide glutathione (GSH) is synthesized by the consecutive action of glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS), where the ligation of cysteine (Cys) and glutamate (Glu) by glutamate-cysteine ligase is the rate-limiting step of glutathione synthesis. 

The cellular import of cystine by the glutamate-cystine antiporter system x_c^- constitutes an significant route of cysteine supply for glutathione synthesis. 

Cysteine is also required for other important cellular antioxidants including thioredoxin (Trx) and thioredoxin reductase (TrxR). 

Ferroptosis occurs when the Gpx4-catalyzed reduction of lipid hydroperoxides is insufficient to prevent the iron-mediated generation of lipid radicals (LO^∙). 

This leads to the propagation of lipid peroxidation and culminates in ferroptosis. Ferroptosis can be experimentally induced by inhibiting Gpx4 via the small molecule inhibitor RSL3, or by limiting glutathione supply to Gpx4. The latter is induced by direct [e.g., buthionine sulfoximine (BSO)] or indirect (e.g., by limiting cysteine availability) inhibition of glutathione synthesis. Cysteine supply is disrupted by inhibitors of system x_c^- including erastin, sulfasalazine, and sorafenib.

 Ferroptosis can also be inhibited by iron chelators such as deferoxamine and deferiprone, and lipid radical scavengers such as ferrostatin-1, liproxstatin-1, and vitamin E. Factors transcriptionally regulated by Nrf2 are indicated in blue italics, whereas factors promoting ferroptosis are indicated in red. Clearly Nrf2 signaling is likely to have an integral and pervasive impact on the manifestation of ferroptosis. 

2) 
NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Dodson M et al. Redox Biol. (2019)Abstract
The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the cellular antioxidant response, controlling the expression of genes that counteract oxidative and electrophilic stresses. Many pathological conditions are linked to imbalances in redox homeostasis, illustrating the important role of antioxidant defense systems in preventing the pathogenic effects associated with the accumulation of reactive species. In particular, it is becoming increasingly apparent that the accumulation of lipid peroxides has an important role in driving the pathogenesis of multiple disease states. A key example of this is the recent discovery of a novel form of cell death termed ferroptosis. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death cascade that has become a key target in the development of anti-cancer therapies, as well as the prevention of neurodegenerative and cardiovascular diseases.
 In this review, we will provide a brief overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. We will also highlight the role of the NRF2 signaling pathway in mediating lipid peroxidation and ferroptosis, focusing on established NRF2 target genes that mitigate these pathways, as well as the relevance of the NRF2-lipid peroxidation-ferroptosis axis in disease.