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.
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
( 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 xc- 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 xc- 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.
