This is a an amazing recent review going in depth on the role of lipid peroxidation in causing iron accumulation and iron accumulation in turn causing more lipid peroxidation. The analysis looks into the role this plays in neurodegeneration, but I think it’s more than likely that this cycle takes place in all aging tissues. I would highly encourage everyone to read the full article.
www.ncbi.nlm.nih.gov
“Neurodegenerative diseases are caused by complex neuronal cell death mechanisms involving iron accumulation and lipid peroxidation in different areas of the brain (Guiney et al., 2017). Neuronal cell death frequently occurs by ferroptosis, a cell death process dependent on iron-mediated lipid peroxidation. Moreover, abnormal iron homeostasis is associated with iron overload, which destroys proteins and lipids through Fenton reactions (Ke and Qian, 2007; Wu et al., 2019). Thus, iron is essential in the initiation and progression of neurodegenerative diseases (Ward et al., 2014). Excessive iron accumulation and lipid peroxidation in these diseases are frequently accompanied by oxidative stress, mitochondrial dysfunction, increased iron content in lipofuscin, and autophagy dysregulation (Ke and Qian, 2007; Álvarez-Córdoba et al., 2019; Corti et al., 2020).”
“It has been reported that 4-HNE-induced neuronal loss and α-synuclein (α-Syn) aggregation is commonly associated with neurodegenerative disorders (Peña-Bautista et al., 2019). Furthermore, it has been reported that oligomeric α-Syn induces lipid peroxidation (Angelova et al., 2015). Recently, Angelova et al. (2020) have reported that oligomeric α-Syn produces an iron-dependent increase in ROS and lipid peroxidation, which in turn induce α-Syn aggregation in membranes, disrupt calcium flux, and lead to ferroptosis. These findings suggest a crucial role of lipid peroxidation and ferroptosis in neurodegenerative diseases (Angelova et al., 2020). Moreover, a positive feedback loop of iron accumulation, mitochondrial dysfunction, and ROS damage that causes α-Syn aggregation, changes in mitochondrial dynamics, proteasomal dysfunction, and activation of cell death pathways has been reported (Urrutia et al., 2014). Studies have reported that lipid peroxidation by-products, 4-HNE and malondialdehyde among others, produce selective protein-modifications by Michael adduction in Alzheimer’s disease (Sultana et al., 2013). This indicates that lipid peroxidation is an early event in Alzheimer’s disease progression and that the levels of lipid peroxidation by-products and protein adducts may be used as biomarkers of disease progression and severity. Moreover, relationship between lipid peroxidation in Alzheimer’s disease and transition-metals through its interaction with amyloid-β, the major component of senile plaques, has been established. Amyloid-β can chelate transition-metals forming aggregates that have pro-oxidant properties (Arlt et al., 2002). In addition, neuronal death in Alzheimer’s disease has been associated with ferroptosis (Angelova et al., 2021).”
“Studies describing that iron accumulation in lipofuscin may originate from damaged mitochondria have been previously reported (Frolova et al., 2015; Álvarez-Córdoba et al., 2019; Kakimoto et al., 2019). In addition, lipofuscin recruits iron resulting in a redox-active surface that catalyzes the Fenton reaction and increases the formation of free radicals (Höhn and Grune, 2013), and consequently, enhance lipid peroxidation. The ability of lipofuscin to inhibit the degradation of oxidized proteins by competitively binding and sequestering the proteasome, a major characteristic, has previously been demonstrated (Sitte et al., 2001).”
“Villalón-García et al. (2022) assessed iron and lipofuscin accumulation by the induction of lipid peroxidation with tert-Butyl peroxide, a radical initiator of lipid peroxidation, with the aim of replicating PLAN pathophysiology. They observed that the induction of lipid peroxidation in healthy control cells promoted iron/lipofuscin accumulation and the supplementation of the control cells with iron-induced lipid peroxidation (Villalón-García et al., 2022). Based on these findings from PLAN and control cellular models, they concluded that lipid peroxidation essentially induces iron/lipofuscin accumulation and iron/lipofuscin accumulation induces lipid peroxidation in a vicious cycle.”
“Vitamin E, a blocker of lipid peroxidation propagation and an efficient ferroptosis inhibitor, has been reported to reduce lipid peroxidation and iron/lipofuscin accumulation and correct mitochondrial dysfunction and the main pathological alterations in PLAN cellular models (Villalón-García et al., 2022).”
“excessive ROS-induced autophagy can lead to autophagic cell death. In addition, lipid peroxidation can induce autophagic dysfunction, triggering autophagic cell death in certain conditions through the inhibition of AMP-activated protein kinase, and consequently, the activation of the mammalian target of rapamycin pathway (Su et al., 2019)”
“Lipid peroxidation by-products form adducts with proteins involved in autophagosome and autolysosome formation thereby decreasing autophagic flux (Dodson et al., 2017), and hinder the timely renewal of organelles such as mitochondria. Moreover, lipid peroxidation may induce lysosomal dysfunction and lipofuscinogenesis, contributing to decreased autophagy (Su et al., 2019). The defective degradation of damaged organelles can facilitate iron accumulation and lipofuscin formation (Moreno-García et al., 2018).”
“A deficient autophagy/mitophagy with incomplete lysosomal degradation has been associated with lipofuscin accumulation, while the enhancement of autophagy/mitophagy alleviates lipofuscin accumulation (Li et al., 2021).”
“Lipid peroxidation by-products have been described as inducers of autophagy and an excess of this process promotes ferroptosis, suggesting a complex feedback between autophagy, ferroptosis, and organelle damage (Tang et al., 2021). In addition, the role of lipoxygenases and Cytochrome P450 oxidoreductase in initiation of lipid peroxidation and ferroptosis has been suggested (Maiorino et al., 2018; Zou et al., 2020; Jiang et al., 2021).”
“excessive oxidative stress accumulation may increase free iron (Latunde-Dada, 2017); however, iron accumulation through Fenton reactions could cause GSH depletion during ferroptosis (Bertrand, 2017), while Fenton reactions cause lipid peroxidation (Bertrand, 2017).
Simultaneous occurrence of all these events causes ferroptosis because the inhibition of any one of these events prevents ferroptosis”
“The reduction of iron accumulation by iron-chelators, such as deferoxamine (Bertrand, 2017; Latunde-Dada, 2017; Chen et al., 2020), or the inhibition of an iron metabolism transcription factor such as iron-responsive element-binding protein 2, inhibit ferroptosis (Li et al., 2020). Furthermore, the action of vitamin E, suppressing the propagation of lipid peroxidation, induces a protective effect against ferroptosis (Latunde-Dada, 2017).”
“The presence of iron accumulation needs the simultaneous depletion of GSH because in cells with high free iron levels, the inhibition of System Xc– is needed to decrease GSH levels to undergo ferroptosis (Bertrand, 2017). In summary, the presence of redox-active iron is simultaneously needed with lipid peroxidation accumulation, low levels of GSH, and decreased GXP4 activity to trigger ferroptosis (Bertrand, 2017).”
“Lipid peroxidation increases permeability of lysosomal membranes resulting in the leakage of free iron into the cytosol and causing Fenton reactions that cause oxidative stress and more lipid peroxidation (Bertrand, 2017). Lipid peroxidation by-products such as 4-HNE contribute to depletion of GSH, since 4-HNE is detoxified by the interaction with GSH through its Cys residue (Sultana et al., 2013). Concurrently, Fenton radicals have been associated with the depletion of GSH reserves (Bertrand, 2017).”
“Ferroptosis is crucially involved in neurological diseases, including neurodegeneration, neurotrauma, and stroke (Reichert et al., 2020). Cellular features of ferroptosis have been observed in dopaminergic neurons in Parkinson’s disease (Do Van et al., 2016), Alzheimer’s disease (Yan and Zhang, 2019), and in neuronal cell death in Huntington’s disease (Zhou et al., 2022).”
“Lipid peroxidation in iron-rich organelles such as mitochondria and defective membrane-dependent processes such as autophagy/mitophagy or vesicle traffic may lead to iron accumulation in lipofuscin, which in turn increases lipid peroxidation. This negative series of events that reinforce each other may aggravate and accelerate the progression of neurodegenerative diseases.”
Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration
Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial ...
www.ncbi.nlm.nih.gov
“Neurodegenerative diseases are caused by complex neuronal cell death mechanisms involving iron accumulation and lipid peroxidation in different areas of the brain (Guiney et al., 2017). Neuronal cell death frequently occurs by ferroptosis, a cell death process dependent on iron-mediated lipid peroxidation. Moreover, abnormal iron homeostasis is associated with iron overload, which destroys proteins and lipids through Fenton reactions (Ke and Qian, 2007; Wu et al., 2019). Thus, iron is essential in the initiation and progression of neurodegenerative diseases (Ward et al., 2014). Excessive iron accumulation and lipid peroxidation in these diseases are frequently accompanied by oxidative stress, mitochondrial dysfunction, increased iron content in lipofuscin, and autophagy dysregulation (Ke and Qian, 2007; Álvarez-Córdoba et al., 2019; Corti et al., 2020).”
“It has been reported that 4-HNE-induced neuronal loss and α-synuclein (α-Syn) aggregation is commonly associated with neurodegenerative disorders (Peña-Bautista et al., 2019). Furthermore, it has been reported that oligomeric α-Syn induces lipid peroxidation (Angelova et al., 2015). Recently, Angelova et al. (2020) have reported that oligomeric α-Syn produces an iron-dependent increase in ROS and lipid peroxidation, which in turn induce α-Syn aggregation in membranes, disrupt calcium flux, and lead to ferroptosis. These findings suggest a crucial role of lipid peroxidation and ferroptosis in neurodegenerative diseases (Angelova et al., 2020). Moreover, a positive feedback loop of iron accumulation, mitochondrial dysfunction, and ROS damage that causes α-Syn aggregation, changes in mitochondrial dynamics, proteasomal dysfunction, and activation of cell death pathways has been reported (Urrutia et al., 2014). Studies have reported that lipid peroxidation by-products, 4-HNE and malondialdehyde among others, produce selective protein-modifications by Michael adduction in Alzheimer’s disease (Sultana et al., 2013). This indicates that lipid peroxidation is an early event in Alzheimer’s disease progression and that the levels of lipid peroxidation by-products and protein adducts may be used as biomarkers of disease progression and severity. Moreover, relationship between lipid peroxidation in Alzheimer’s disease and transition-metals through its interaction with amyloid-β, the major component of senile plaques, has been established. Amyloid-β can chelate transition-metals forming aggregates that have pro-oxidant properties (Arlt et al., 2002). In addition, neuronal death in Alzheimer’s disease has been associated with ferroptosis (Angelova et al., 2021).”
“Studies describing that iron accumulation in lipofuscin may originate from damaged mitochondria have been previously reported (Frolova et al., 2015; Álvarez-Córdoba et al., 2019; Kakimoto et al., 2019). In addition, lipofuscin recruits iron resulting in a redox-active surface that catalyzes the Fenton reaction and increases the formation of free radicals (Höhn and Grune, 2013), and consequently, enhance lipid peroxidation. The ability of lipofuscin to inhibit the degradation of oxidized proteins by competitively binding and sequestering the proteasome, a major characteristic, has previously been demonstrated (Sitte et al., 2001).”
“Villalón-García et al. (2022) assessed iron and lipofuscin accumulation by the induction of lipid peroxidation with tert-Butyl peroxide, a radical initiator of lipid peroxidation, with the aim of replicating PLAN pathophysiology. They observed that the induction of lipid peroxidation in healthy control cells promoted iron/lipofuscin accumulation and the supplementation of the control cells with iron-induced lipid peroxidation (Villalón-García et al., 2022). Based on these findings from PLAN and control cellular models, they concluded that lipid peroxidation essentially induces iron/lipofuscin accumulation and iron/lipofuscin accumulation induces lipid peroxidation in a vicious cycle.”
“Vitamin E, a blocker of lipid peroxidation propagation and an efficient ferroptosis inhibitor, has been reported to reduce lipid peroxidation and iron/lipofuscin accumulation and correct mitochondrial dysfunction and the main pathological alterations in PLAN cellular models (Villalón-García et al., 2022).”
“excessive ROS-induced autophagy can lead to autophagic cell death. In addition, lipid peroxidation can induce autophagic dysfunction, triggering autophagic cell death in certain conditions through the inhibition of AMP-activated protein kinase, and consequently, the activation of the mammalian target of rapamycin pathway (Su et al., 2019)”
“Lipid peroxidation by-products form adducts with proteins involved in autophagosome and autolysosome formation thereby decreasing autophagic flux (Dodson et al., 2017), and hinder the timely renewal of organelles such as mitochondria. Moreover, lipid peroxidation may induce lysosomal dysfunction and lipofuscinogenesis, contributing to decreased autophagy (Su et al., 2019). The defective degradation of damaged organelles can facilitate iron accumulation and lipofuscin formation (Moreno-García et al., 2018).”
“A deficient autophagy/mitophagy with incomplete lysosomal degradation has been associated with lipofuscin accumulation, while the enhancement of autophagy/mitophagy alleviates lipofuscin accumulation (Li et al., 2021).”
“Lipid peroxidation by-products have been described as inducers of autophagy and an excess of this process promotes ferroptosis, suggesting a complex feedback between autophagy, ferroptosis, and organelle damage (Tang et al., 2021). In addition, the role of lipoxygenases and Cytochrome P450 oxidoreductase in initiation of lipid peroxidation and ferroptosis has been suggested (Maiorino et al., 2018; Zou et al., 2020; Jiang et al., 2021).”
“excessive oxidative stress accumulation may increase free iron (Latunde-Dada, 2017); however, iron accumulation through Fenton reactions could cause GSH depletion during ferroptosis (Bertrand, 2017), while Fenton reactions cause lipid peroxidation (Bertrand, 2017).
Simultaneous occurrence of all these events causes ferroptosis because the inhibition of any one of these events prevents ferroptosis”
“The reduction of iron accumulation by iron-chelators, such as deferoxamine (Bertrand, 2017; Latunde-Dada, 2017; Chen et al., 2020), or the inhibition of an iron metabolism transcription factor such as iron-responsive element-binding protein 2, inhibit ferroptosis (Li et al., 2020). Furthermore, the action of vitamin E, suppressing the propagation of lipid peroxidation, induces a protective effect against ferroptosis (Latunde-Dada, 2017).”
“The presence of iron accumulation needs the simultaneous depletion of GSH because in cells with high free iron levels, the inhibition of System Xc– is needed to decrease GSH levels to undergo ferroptosis (Bertrand, 2017). In summary, the presence of redox-active iron is simultaneously needed with lipid peroxidation accumulation, low levels of GSH, and decreased GXP4 activity to trigger ferroptosis (Bertrand, 2017).”
“Lipid peroxidation increases permeability of lysosomal membranes resulting in the leakage of free iron into the cytosol and causing Fenton reactions that cause oxidative stress and more lipid peroxidation (Bertrand, 2017). Lipid peroxidation by-products such as 4-HNE contribute to depletion of GSH, since 4-HNE is detoxified by the interaction with GSH through its Cys residue (Sultana et al., 2013). Concurrently, Fenton radicals have been associated with the depletion of GSH reserves (Bertrand, 2017).”
“Ferroptosis is crucially involved in neurological diseases, including neurodegeneration, neurotrauma, and stroke (Reichert et al., 2020). Cellular features of ferroptosis have been observed in dopaminergic neurons in Parkinson’s disease (Do Van et al., 2016), Alzheimer’s disease (Yan and Zhang, 2019), and in neuronal cell death in Huntington’s disease (Zhou et al., 2022).”
“Lipid peroxidation in iron-rich organelles such as mitochondria and defective membrane-dependent processes such as autophagy/mitophagy or vesicle traffic may lead to iron accumulation in lipofuscin, which in turn increases lipid peroxidation. This negative series of events that reinforce each other may aggravate and accelerate the progression of neurodegenerative diseases.”
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