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NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases
Open accessAbstract
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.
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Written from the paper’s full text.
TL;DR
NOX4 protein is elevated in impaired astrocytes in AD patient cortex and APP/PS1 mouse cortex, where lipid peroxidation markers 4-HNE and MDA are also increased. In human astrocytes, NOX4 overexpression impairs mitochondrial metabolism, induces oxidative stress and antioxidant suppression, and promotes ferroptosis-like lipid peroxidation and cytotoxicity.
Key findings
- NOX4 levels were significantly elevated in GFAP-positive impaired astrocytes in AD cortex versus non-AD cortex (n = 3 per group, n = 10 images per subject; p < 0.01) and in APP/PS1 mouse cortex versus WT (n = 5 per group, n = 10 images per subject; p < 0.01).
- Oxidative stress-induced lipid peroxidation markers 4-HNE and MDA were significantly elevated in impaired astrocytes of AD patients and APP/PS1 mice, and 4-HNE co-localized with NOX4-positive astrocytes (p < 0.01).
- In human astrocytes, NOX4 overexpression significantly suppressed basal and oligomycin/FCCP-responsive oxygen consumption rate, reduced mitochondrial ATP production, and reduced protein levels of all five mitochondrial ETC complexes: Complex I NDUFB8, Complex II SDHB, Complex III UQCRC2, Complex IV MTCO1, and Complex V ATP5F1A (p < 0.05 or p < 0.01).
- NOX4 overexpression increased mtROS and mitochondrial fragmentation, reduced GSH and GSH/GSSG, increased GSSG, inhibited NRF2 nuclear translocation and HO-1/GCL, and increased 4-HNE, MDA, iron accumulation, morphological cell death, and LDH cytotoxicity (p < 0.05 or p < 0.01).
Methods
- Postmortem human brain tissues: 12 paraffin-embedded tissues from 3 AD donors (frontal, occipital, temporal, parietal cortex) and 4 normal adult brain tissues from 4 donors; immunofluorescence analyzed NOX4, 4-HNE, MDA, GFAP, and Tomm20. APP/PS1 double-transgenic mice were compared with WT mice.
- Human astrocytes were transduced with pCMV6-AC-GFP-NOX4 or vector. Assays included Seahorse XF96e OCR and real-time ATP rate, immunoblot for mitochondrial ETC complexes, MitoSOX flow for mtROS, GSH/GSSG and GSSG measurements, NRF2 nuclear/cytosolic fractionation, HO-1 and GCL levels/activity, iron colorimetric assay, LDH cytotoxicity, and 3D imaging.
- Statistics used Shapiro-Wilk and Levene’s tests, two-tailed Student’s t-test for two groups, and ANOVA with Dunnett’s post hoc for multiple groups; significance was p < 0.05, p < 0.01, or p < 0.001.
Limitations
- Stated: it remains unclear whether the impaired astrocytes with high NOX4 have reactive astrocyte function in AD, and further study is needed on the role of NOX4 in reactive astrocytes. The authors also state that further study is needed to identify secreted molecules from NOX4-induced ferroptosis as potential diagnostic markers.
- Evident from the text: the human sample is small (3 AD donors and 4 normal donors), and the mechanistic causality in human astrocytes relies mainly on NOX4 overexpression; the text does not report NOX4 knockdown, NOX4 inhibition, or ferroptosis-blockade rescue experiments.
- Evident from the text: APP/PS1 mouse data are descriptive immunofluorescence comparisons, without in vivo NOX4 manipulation reported.
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58 Own result · 40 Not checked yet · 20 Own interpretation · 4 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”
- Also stated in: § Introduction · plain
“We found that the elevation of NOX4 promotes the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § Introduction · plain
“The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged
“These results suggest that the levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of patients with AD.”
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · plain
“The levels of 4-HNE and MDA were generally higher in every individual patient with AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”
- Also stated in: § Introduction · plain
“The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD.”
- Also stated in: § Introduction · plain
“Here, our results showed that the levels of NOX4 were significantly elevated in impaired astrocytes in patients with AD and APP/PS1 double-transgenic mouse model of AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes.”
- Also stated in: § Introduction · plain
“The elevation of NOX4 induced mtROS production and mitochondrial fragmentation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes.”
- Also stated in: § Introduction · plain
“Notably, the elevation of NOX4 induced ferroptosis-dependent cytotoxicity by the activation of lipid peroxidation in human astrocytes.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD.”
- Also stated in: § Introduction · plain
“The levels of 4-HNE and MDA were also significantly elevated in impaired astrocytes of patients with AD and mouse AD.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, the number of impaired astrocytes which have the positive subcellular co-localization between NOX4 and GFAP was significantly increased in patients with AD (AD) (Fig. 1C).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 5
- Probably not a substantial claim. 35
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the length of GFAP-positive filaments was shortened and the shape of GFAP-positive filaments showed shrinkage in astrocytes of patients with AD (AD) compared to non-AD donor (Normal) (Fig. 1A).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“NOX4 produces ROS constitutively [37].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [37] Serrander, 2007, NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation, Biochem. J. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The impairment of mitochondrial ETC activity in mitochondrial metabolism leads to an increase of reactive oxygen species (ROS) production which occurs mainly at Complex I and Complex III [31].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [31] Nemoto, 2000, Role for mitochondrial oxidants as regulators of cellular metabolism, Mol. Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Among NOX isoforms, NOX4 is a major isoform in astrocytes [36].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [36] Nayernia, 2014, New insights on NOX enzymes in the central nervous system, Antioxidants Redox Signal. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“The excessive production of ROS and the activation of lipid peroxidation are linked to ferroptosis-dependent cell death [32,33].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [32] Stockwell, 2017, Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biol. Dis. Cell
- Not checked yetcites [33] Stockwell, 2020, The chemistry and biology of ferroptosis, Cell Chem Biol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are random, independent, normally distributed, and have a common variance.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of supportive function by impaired astrocytes has been implicated in neurodegenerative diseases via neuronal death [21,22].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [21] Phatnani, 2015, Astrocytes in neurodegenerative disease, Cold Spring Harb Perspect Biol source
- Not checked yetcites [22] Karkkainen, 2012, Brain environment and Alzheimer's disease mutations affect the survival, migration and differentiation of neural progenitor cells, Curr. Alzheimer Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Recent studies suggest that oxidative stress is a critical factor that contributes to the initiation and progression of AD [[2], [3], [4]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [[2], [3], [4]]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“Mitochondrial dysfunction plays an important role in the pathogenesis of AD as an early feature of AD [5,6].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [5] Perez Ortiz, 2019, Mitochondrial dysfunction in Alzheimer's disease: role in pathogenesis and novel therapeutic opportunities, Br. J. Pharmacol. source
- Not checked yetcites [6] Wood, 2020, Mitochondrial dysfunction manifests in the early stages of Alzheimer disease, Nat. Rev. Neurol.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“Recent studies have shown the impairment of mitochondrial metabolism by multiple mitochondrial alterations in major neurodegenerative diseases such as AD and Parkinson's disease (PD) [[11], [12], [13]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [[11], [12], [13]]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mitochondrial damage has been found to be involved in lipid peroxidation and imbalance of iron homeostasis in neurodegenerative diseases such as AD and PD [34].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Introduction
What the sources say
- Not checked yetcites [34] Conrad, 2018, Regulation of lipid peroxidation and ferroptosis in diverse species, Genes Dev. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure objectivity, all measurements were performed with blinded conditions by two observers per experiment under identical conditions.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Immunofluorescence analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“NOX4 is linked to oxidative stress and ROS production in brain injury [42,43].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [42] Casas, 2017, NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage, Proc. Natl. Acad. Sci. U. S. A. source
- Not checked yetcites [43] Ma, 2018, Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury, Free Radic. Biol. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondrial dysfunction has been associated with the pathogenesis of AD [5,6].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [5] Perez Ortiz, 2019, Mitochondrial dysfunction in Alzheimer's disease: role in pathogenesis and novel therapeutic opportunities, Br. J. Pharmacol. source
- Not checked yetcites [6] Wood, 2020, Mitochondrial dysfunction manifests in the early stages of Alzheimer disease, Nat. Rev. Neurol.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Oxidative stress is linked to amyloid-beta (Aβ) toxicity in AD [44,45].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The levels of cerebral blood (CBF) and cerebral metabolic rate for oxygen (CMRO2) in the medial temporal region were decreased in patient with AD [38].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [38] Ishii, 1996, Decreased medial temporal oxygen metabolism in Alzheimer's disease shown by PET, J. Nucl. Med.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In APP/PS1 mouse model of AD, the elevation of NOX activity is linked to cognitive impairment [47].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [47] Bruce-Keller, 2011, Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation, Neurobiol. Dis. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Since NOX4 is a constitutively active form among the NOX isoforms, the activity of NOX4 depends on its expression [37].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [37] Serrander, 2007, NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation, Biochem. J. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“the high levels of ceramide contribute to formation of amyloid β-peptides [[81], [82], [83]]”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [81], [82], [83]
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“the role of lipid peroxidation has been discovered in cell dysfunction and death during neuronal degeneration [74,75]”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [74] Mattson, 1998, Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity, Trends Neurosci. source
- Not checked yetcites [75] Keller, 1998, Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system, Rev. Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“High levels of 4-HNE found in pathological conditions or diseases which are associated with cellular stress and dysfunction, cellular damage and pro-apoptotic signaling [[68], [69], [70], [71], [72], [73]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [68], [69], [70]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Ferroptosis-derived dead cells can release damage-associated molecular patterns (DAMPs) and lipid metabolites that can cause an elevation of inflammation [76,77].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Reactive aldehydes from lipid peroxidation have biological active functions [59].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [59] Esterbauer, 1991, Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes, Free Radic. Biol. Med. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The high production of ROS is associated with excessive intracellular lipid accumulation such as diacylglycerol (DAG) and ceramide [[78], [79], [80]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [78], [79], [80]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A previous study has shown that a product of lipid peroxidation is increased in brain of patients with AD [55].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [55] Markesbery, 1998, Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease, Neurobiol. Aging source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The role of reactive astrocytes remains unclear in terms of plaque formation, Aβ clearance and plaque growth restriction [50,51].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Also, mitochondrial dysfunction including the excessive production of mtROS contributes to the induction of neuronal apoptosis [[84], [85], [86]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [84], [85], [86]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For immunoblots, β-actin was used as a loading control.”
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
“For immunoblots, Histone H3 (nuclear) and β-actin (cytosolic) was used as a loading control.”
- Also stated in: § NOX4 promotes ferroptosis by oxidative stress-induced lipid peroxidation in human astrocytes · plain
“For immunoblots, β-actin was used as a loading control.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
In the paper
“The redox imbalance and oxidative stress are linked to neurodegeneration in AD [[1], [2], [3], [4]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [1], [2], [3]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the accumulation of ceramide may have the effects of neurotoxicity in AD”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data are representative of three independent experiments.”
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
“Data are representative of three independent experiments.”
- Also stated in: § The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes · plain
“Data are representatives of three independent experiments.”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Also stated in: § NOX4-induced mitochondrial metabolic impairment induces oxidative stress by inhibition of cellular antioxidant process in human astrocytes · plain
In the paper
“4-HNE, an electrophilic lipid peroxidation product, also has various cytotoxic effects of lipid peroxidation such as depletion of glutathione, dysfunction of structural proteins, reduction in enzyme activities, and induction of cell death [60].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [60] Craighead, 1995
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Based on hormetic effects of 4-HNE, low physiological levels of 4-HNE can provide positive effects on cell function including cell proliferation and signaling pathway such as tyrosine kinase receptor (TKR) activation and downstream kinase signaling [[61], [62], [63], [64], [65], [66], [67]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [61], [62], [63]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In pathogenesis of neurodegenerative diseases, the high levels of 4-HNE are involved in oxidative stress of AD or Parkinson's diseases [[70], [71], [72], [73]].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [70], [71], [72]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The abundant diffusible products of lipid peroxidation are chemically reactive aldehydes including malondialdehyde (MDA), acrolein, 4-hydroxy-2-hexenal (4-HHE), and 4-hydroxy-2-nonenal (4-HNE) [57,58].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [57] Schneider, 2001, Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals, J. Biol. Chem. source
- Not checked yetcites [58] Porter, 1995, Mechanisms of free radical oxidation of unsaturated lipids, Lipids source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Similarly, a recent study has suggested that NOX4 in pericytes is the major source of ROS which is involved in the constriction of capillaries early in the response to Aβ [48].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [48] Nortley, 2019, Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes, Science source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Regarding the form of astrocytes, reactive astrocytes are an activated form of astrocytes in response to toxic materials [49].”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Discussion
What the sources say
- Not checked yetcites [49] Wilhelmsson, 2006, Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury, Proc. Natl. Acad. Sci. U. S. A. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The mechanisms by which NOX4 regulates ferroptosis of astrocytes by oxidative stress via impairment of mitochondrial metabolism in AD remain unclear.
“However, the mechanisms by which NOX4 regulates ferroptosis of astrocytes by oxidative stress via impairment of mitochondrial metabolism in AD remains unclear.”
The paper relies on this without support.
4-HNE is a marker for ferroptosis.
“Since the levels of 4-HNE, a marker for ferroptosis, were elevated in impaired astrocytes of patients with AD”
The paper relies on this without support.
Iron accumulation is a specific marker of ferroptosis.
“the accumulation of iron, a specific marker of ferroptosis”
The paper relies on this without support.
APP/PS1 mice model AD.
“APP/PS1 double-transgenic mouse model of AD”
The paper relies on this without support.
NRF2 is a key regulator of the cellular antioxidant response.
“nuclear factor erythroid 2–related factor 2 (NRF2) signaling pathway, a key regulator of the cellular antioxidant response”
The paper relies on this without support.
HO-1 and GCL are target genes of NRF2.
“heme oxygenase-1 (HO-1) (Fig. 6E and F) and glutamate cysteine ligase (GCL) (Fig. 6E and F) as target genes of NRF2”
The paper relies on this without support.
Mitochondrial fragmentation indicates mitochondrial impairment.
“We next analyzed morphological impairment of mitochondria caused by NOX4 over-expression through immunofluorescence staining with Tomm20”
The paper relies on this without support.
The upstream molecular target in the regulation of ferroptosis by lipid peroxidation in Alzheimer's disease remains unclear.
“the upstream molecular target in the regulation of ferroptosis by lipid peroxidation in AD remains unclear”
The paper relies on this without support.
NOX4 levels are high in the cortex of patients with Alzheimer's disease.
“the high levels of NOX4, in cortex of patients with AD”
The paper relies on this without support.
It is unclear whether impaired astrocytes in Alzheimer's disease have a function of reactive astrocytes.
“it was unclear whether these impaired astrocytes have a function of reactive astrocytes in AD”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The levels of two products of oxidative damage, 4-HNE and MDA, were also significantly elevated, suggesting that the elevation of NOX4 promotes the impairment of mitochondrial metabolism, mitochondrial ROS production and fragmentation in human astrocytes [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
In the citing paper
“Ferroptosis-dependent cytotoxicity induced by the activation of OS has also been described in human astrocytes from AD patients [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
In the citing paper
“NO X4 is the astrocytes isoform, and its levels are reported significantly elevated in astrocytes of patients with AD and APP/PS1 double-transgenic mouse model of AD [101].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Human subjects study
“A total of four paraffin embedded adult normal brain tissues from four donors including frontal cortex (NBP2-77761), occipital cortex (NBP2-77766), temporal cortex (NBP2-77774) and parietal cortex (NBP2-77769) were obtained from Novus Biologicals”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of NOX4 are elevated in impaired astrocytes of the cortex region from patients with Alzheimer's diseases
“(B) Quantification of intensity for NOX4 positive staining in astrocytes from immunofluorescence images in the cerebral cortex region from patients with AD (AD #1, AD #2, AD #3) or non-AD (normal) (n = 3 per group, n = 10 images per individual subject).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Reagents and antibodies
“polyclonal rabbit anti-4-HNE antibody (ab3517, Abcam, Cambridge, UK)”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Materials and methods > Immunofluorescence analysis
“polyclonal rabbit anti-4-HNE antibody (1:100) (ab46545, Abcam, Cambridge, UK)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
“(G) Quantification of cells with mitochondrial fragmentation from immunofluorescence images of mitochondrial morphology in control (Control) and NOX4 overexpressing (NOX4) human astrocytes (n = 10 per group).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The elevation of NOX4 promotes oxidative stress by impairment of mitochondrial metabolism via inhibition of mitochondrial respiration and ATP production in human astrocytes
“(The percent of morphological dead cells in a total of 100 cells of 10 individual images per group was calculated).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from brains of APP/PS1 mice
“Immunofluorescence staining revealed that the intensity of 4-HNE-positive staining in GFAP-positive astrocytes was increased of the cortex region of APP/PS1 mice compared to WT mice (Fig. 4A and C and Fig. S6).”
§ NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases > Results > The levels of oxidative stress-induced lipid peroxidation are elevated in impaired astrocytes of the cortex region from brains of APP/PS1 mice
“(B) Quantification of 4-HNE positive staining in astrocytes from immunofluorescence images in the cortex region from brains of APP/PS1 mice (APP/PS1) or wild-type mice (WT) (n = 5 per group, n = 10 images per individual subject). Data are mean ± standard deviation (SD). **, p < 0.01 by Student's two-tailed t-test. (C) Quantification of 4-HNE positive astrocytes”
Citations
Cites
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695 · cited 2×
“Ferroptosis is a type of programmed cell death that is dependent on iron and the accumulation of lipid peroxides, mainly lipid hydroperoxides, which cause damage to the lipid bilayer of the plasma membrane through accelerated oxidation of membrane lipids [32,33].”
BackgroundThe NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989 · cited 3×
“In most mammals, there are seven NOX isoforms (NOX1, NOX2, NOX3, NOX4, NOX5, dual oxidase (DUOX)1, and DUOX2) [35].”
BackgroundInfluentialChemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90192-6 · Cited by 6,672
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
Alzheimer's Disease: Genes, Proteins, and Therapy
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Oxidative Stress, Glutamate, and Neurodegenerative Disorders
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
Neurodegenerative diseases and oxidative stress
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Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · cited 1×
“As the driving force of ferroptosis, a high level of lipid peroxidation can disrupt cellular function [56].”
BackgroundOxidative stress hypothesis in Alzheimer’s disease
Markesbery, W. R. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00629-6 · Cited by 2,383 · cited 1×
“Oxidative stress is characterized by the over-production of reactive oxygen species (ROS), damage of the mitochondrial respiratory chain, and imbalance of Ca2+ homeostasis [9,10].”
Background
Research works printed but not linked: 1
- Stockwell, 2017, Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biol. Dis. Cell, 171, 273
Cited by
Sorted by citations
Items 601–679 of 679
Xing, X., Ren, J., Zhu, Y., Lin, Y., Xu, Z., Chen, L., Wang, X., Zhang, C., & Xiang, L. F. (2026) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2025.12.022 · Cited by 1
Zhang, X., Ding, W., Guo, C., et al. (2026) · Behavioural Brain Research · doi:10.1016/j.bbr.2026.116040
Yehia, A., Toufaily, C., Ghaffar, D. M. A., Wakeel, G. E., Adel, M., Mostafa, A., & Abulseoud, O. A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031526
“…and anxiety-like behavior [4,5], bipolar disorder [6], ischemic stroke [7,8], traumatic brain injury and its neuropsychiatric complications [9,10], Alzheimer’s [11–13], Parkinson’s [14,15], multiple sclerosis [16,17], amyotrophic lateral sclerosis [18,19], and possibly post-COVID syndrome [20].”
Chen, H., Chen, Z., Cao, K., et al. (2026) · Discover Oncology · doi:10.1007/s12672-026-04562-8
“NADPH oxidase 4 (NOX4) promotes ferroptosis by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism [41].”
Xu, L., Li, Y., He, Z., Chen, W., & Li, Y. (2026) · Pathology - Research and Practice · doi:10.1016/j.prp.2026.156423 · Cited by 1
Chai, C., Liu, L., Wang, R., et al. (2026) · Brain Research · doi:10.1016/j.brainres.2026.150236
Liang, W., Liu, X., Wei, Y., Liu, X., Fan, Z., Yu, P., & Yang, P. (2026) · Functional & Integrative Genomics · doi:10.1007/s10142-026-01834-y
Ji, R., Zang, Z., Sun, Y., Fu, X., Lan, S., Li, X., Guo, L., Liu, X., Peng, C., Wang, M., et al. (2026) · Fitoterapia · doi:10.1016/j.fitote.2026.107162 · Cited by 2
Chapa‐Dubocq, X. R., Vita, S. M., Guzman‐Hernandez, R. A., & Molina, P. E. (2026) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.70267 · Cited by 1
Zhou, J., Lu, P., He, H., et al. (2026) · Cellular Signalling · doi:10.1016/j.cellsig.2026.112507
Tao, M., Du, X., Chen, Q., Mu, W., Lou, S.-N., Zhang, X., Xu, M., Li, J., Guo, Y., Zhu, W., et al. (2026) · Cell Proliferation · doi:10.1111/cpr.70207
“Pathway enrichment analysis of these DEGs revealed that lipid metabolism–related pathways were strongly upregulated in the assembloids (Figure 3f), suggesting that cortical input promotes lipid resistance in hypothalamic neurons [26, 27].”
NOX4 mediates ferroptosis through oxidative stress in diabetic keratopathy
Wang, X., Wang, Y., Wang, Y., et al. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111008
Guo, F., Feng, H., Sun, R., Yan, J., Ge, Y., Liu, X., Zhang, X., Zhang, X., Zhang, X., & Liu, Y. (2026) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2026.139961
Greco, D., Das, D., Novotný, J., Olsen, M. J., & Telenský, P. (2026) · Scientific Reports · doi:10.1038/s41598-026-47881-0
“A recent study demonstrated that NADPH oxidase 4 (NOX4), contributes to astrocyte ferroptosis through oxidative stress-induced lipid peroxidation and mitochondrial dysfunction, identifying NOX4 as a potential target for the treatment of Alzheimer’s disease 43 .”
Ferroptosis and Pyroptosis: Association with Three Types of Neurodegenerative Diseases
刘, 睿. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.1641658
Wang, Z., Jiang, X., Lin, J., An, R., He, Y., & Li, S. (2026) · Antioxidants · doi:10.3390/antiox15040515 · Cited by 1
“As mitochondria are important energy metabolism organelles within cells, abnormalities in mitochondria directly lead to neuronal damage [35].”
Silica Promotes Silicosis via the ROS/NF‐κB p65 Signaling‐Activated Hypoxia–Lactate Axis in Rats
Fu, Y.-Y., Zhou, Y., Hu, H.-J., Liu, Y.-R., Zhang, Z.-Q., & Han, G.-Z. (2026) · Journal of Applied Toxicology · doi:10.1002/jat.70209
“Levels of total glutathione, GSH, GSSG, and the GSH/GSSG ratio were used to assess the antioxidant capacity of lung against redox environment (P. Li et al. 2016; Park et al. 2021).”
Svobodová, I., Bendová, Z., & Novotný, J. (2026) · Journal of Integrative Neuroscience · doi:10.31083/jin49765 · Cited by 2
Natural Products for Alzheimer’s Disease: A New Twist Impacting Ferroptosis
易亚乔, Jia, P., Xie, P., Peng, X., Zhu, X., Yin, S., Yan, C., & Yu, G. (2026) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x26500266
Liao, Q., Liu, S., Wei, L., et al. (2025) · Molecular vision · doi:10.63500/mv_v31_515
Wang, X., Lin, Y., Liu, W., Wu, Y., Yang, B., Qi, Y., Zhang, Y., Jin, Y., Wang, Y., Niu, K., et al. (2026) · Biomedicines · doi:10.3390/biomedicines14051040
“NOX4 is a member of the NADPH oxidase family and possesses the ability to catalyze the production of an excessive amount of reactive oxygen species (ROS), thereby triggering oxidative stress in cells [30].”
Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights
Li, L., Wang, S., Duan, L., Zhang, L., Yan, H., Chen, X., Tao, L., & Gao, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1807104 · Cited by 1
“…neuronal ferroptosis through multiple mechanisms, including IL-6-mediated activation of the JAK/STAT3 pathway, which induces hepcidin expression and suppresses ferroportin, thereby enhancing neuronal iron retention (72), as well as direct ROS release that accelerates lipid peroxidation (73).”
Li, W., Li, X., Huang, C., Liu, Y., Zx, M., Zhou, Z., Guo, Q., Xia, C., Wang, C., Zhong, Y., et al. (2026) · Chinese Herbal Medicines · doi:10.1016/j.chmed.2026.05.009 · Cited by 1
Kim, Y., Jeon, H., Kwon, S., Chae, S., & Mun, J. Y. (2026) · Cell Structure and Function · doi:10.1247/csf.26019
BRD4 Aggravates Acute Lung Injury by Inducing Ferroptosis in Alveolar Epithelial Cells
Liu, X., Gu, Y., & Yuan, F. (2026) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70803
Zhang, L., Chu, W., Feng, X., et al. (2026) · Biology Direct · doi:10.1186/s13062-026-00835-y
“Ferroptosis is a novel form of cell death triggered by the inactivation of cellular GSH-dependent antioxidant defenses, which leads to iron-dependent accumulation of toxic lipid ROS, thereby affecting the pathological processes of various diseases [23, 31].”
Plumbagin ameliorates multiple sclerosis by inducing DDX3X-mediated stress granule assembly in mice
Fang, M., Liu, Y., Han, Y., Xu, Y., Yu, J., Yan, Y., Jin, Z., Wu, X., Huang, C., & Fan, S. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108257
Cao, S., Lan, D., Wei, Y., Zeng, H., & Zhang, H. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04500-4
Tian, X., Wen, Z., You, Z., Mao, Y., Huang, Q., Zeng, L., Hu, W., Wei, D., Qian, H., Zhang, M., et al. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.05.315 · Cited by 1
Mao, X., Zhou, W., An, W., Zhang, J., Chen, H., Sun, M., & Zhao, H. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.05.313
Ferroptosis and NADPH Oxidases
Cui, S., & Ye, J. (2026) · Springer eBooks · doi:10.1007/978-3-032-21135-4_9
Jiang, X., Wang, Y., Qu, J., et al. (2026) · Biological Trace Element Research · doi:10.1007/s12011-026-05153-y
Ferroptosis in vascular injury of critically ill patients: implications of gut microbiota regulation
Hou, H., Gao, J., Wang, M., Sun, M., Zhang, T., Tian, L., Yang, Z., Chen, M., Lian, G., & Fang, W. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1781905 · Cited by 1
Li, X., Duan, X., Gao, L., Bai, Y., Wang, J., Tong, H., Li, Y., Zhang, S., Xu, Z.-Q. D., & Li, H. (2026) · Behavioural Brain Research · doi:10.1016/j.bbr.2026.116290
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Zheng, H., Xu, G., Yao, H., Guan, A., Ma, R., Zhang, W., Zheng, L., Zhao, Y., & Wang, G. (2026) · Chemical Engineering Journal · doi:10.1016/j.cej.2026.178221 · Cited by 1
Guo, W., Wang, Y., Wang, Y., Ye, J., Zheng, M., & Fan, X. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116994
Deng, L., Li, H., Yang, S., Chen, F., Qiao, J., 包慧中, Wang, X., Fang, S., Xu, B., & Tang, Z. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04654-1
“…of several signaling pathways, including NF-κB-mediated inflammatory activation [72], impaired Nrf2-dependent antioxidant defense [73], aberrant AKT/ GSK-3β signaling associated with tau pathology [74], and ferroptosis-related pathways involved in iron homeostasis and lipid peroxidation [75].”
Gao, L., Hui, R., Tang, Z., Feng, T., Hu, Z., Zhang, X., Jiang, P., Zhao, H., So, K., Luo, T., et al. (2026) · Advanced Science · doi:10.1002/advs.76088
“…in the PrL. Consistent with previous reports that oxidative stress and lipid peroxidation-related processes can disrupt mitochondrial function and contribute to astrocytic injury, these alterations may participate in the reduced structural complexity of astrocytes observed in our model [ 39 ].”
Jiao, J., Shang, J., Yan, M., Wang, B., Wei, W., Cui, Y. R., Zhang, J., & Liu, X. D. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.122060
Xu, H., Li, C., Qin, R., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117056
Jiang, Z., Zhang, J., Zhang, X., Xie, C., Chen, X., Ma, G., Lu, X., Ai, Y., & Jia, T. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05599-w
“Park et al. (2021) reported that NOX4 can aggravate AD by promoting oxidative stress in astrocytes and triggering ferroptosis, and Maimaiti et al. (2024) further high-lighted the contribution of NOX4-mediated glial injury to neurodegenerative disorders.”
Zhao, Y., Pakaprot, N., Sutiwisesak, R., Vattarakorn, U., & Tapechum, S. (2026) · PLoS ONE · doi:10.1371/journal.pone.0352151
“In astrocytes, increased NOX4 expression has been reported in neurodegenerative disease models and is associated with mitochondrial dysfunction, lipid peroxidation, and glial pathology [62].”
ZHANG, Y., Zhu, F., Xiaotian, W. U., Zhansong, L. I., Huang, P., Gao, Y., & Zeng, L. (2026) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2025-0706
Zeng, C., Zhu, J., Lu, R., Wu, P., Li, X., Li, F., Peng, C., 周应芳, & Xue, Q. (2026) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003770 · Cited by 1
“[6,19,20] In EMs, the ROS-buffering capacity of ectopic endometrial stromal cells (ecESCs) is exhausted to protect against oxidative damage; thus, these cells tend to be more sensitive to oxidants.”
Castillo-Mendieta, T., Sánchez‐Torres, S., Salgado‐Ceballos, H., Segura-Uribe, J. J., Morán, J., Guerra‐Araiza, C., & Coyoy-Salgado, A. (2026) · Brain Sciences · doi:10.3390/brainsci16070711
“In contrast, NOX4 is constitutively active once expressed in the membrane together with p22 phox [44,45].”
Iron and lipid dysregulation as key determinants of ferroptosis in cardiometabolic disease
Cho, S., Sung, H. K., Tang, J., Summers, S. A., & Sweeney, G. (2026) · Progress in Lipid Research · doi:10.1016/j.plipres.2026.101395 · Cited by 1
Wang, B., Tang, X., Zhang, H., Jiang, Z. H. E. N. G. M., & Yan, J. (2026) · Journal of Applied Toxicology · doi:10.1002/jat.70311
Guo, Z.-S., Zhang, J., Lv, F., et al. (2026) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2026.2679470
“NOX4, a significant regulator of ROs production, has been demonstrated to facilitate ferroptosis by disrupting mitochondrial oxidative metabolism [55].”
Pan, X., Yang, Y., Liu, C., Xu, L., Yu, J., Ge, S., Wang, W., Wang, C., Wei, W., Wu, S., et al. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.179127
Xu, C. (2026) · Pakistan Journal of Pharmaceutical Sciences · doi:10.36721/pjps.2026.39.10.287.1
Hsu, C.-Y., Raval, A. D., Bainsal, N., Kaur, I., Baig, M. R., Turakulov, R., Sapaev, I., Hjazi, A. M., Alghazali, T., & Smerat, A. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06018-0
“As an NADPH oxidase, NOX4 generates ROS (mainly H ₂ O ₂ ), and when upregulated in stress conditions such as inflammation or Aβ exposure, it drives chronic oxidative damage in endothelial cells, neurons, and glia [80].”
Zhang, X., Xie, Y. D., Wu, Z., Xi, D., Tang, N., Li, X., & Ma, K. (2026) · Chinese Journal of Natural Medicines · doi:10.1016/s1875-5364(26)61195-8
Yuan, J., Sui, S., Yang, Z., Zhang, K., & Hu, Q. (2026) · Journal of Diabetes Investigation · doi:10.1111/jdi.70384
“MDA is a well-known marker of lipid peroxidation, and its increased levels in HG-treated HUVECs further con fi rm the presence of oxidative stress 43 .”
Ding, S., Guo, Z., Ji, H., & He, J. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1879368
“A study conducted by Park et al. reveals that the concentrations of lipid peroxidation byproducts, including 4-HNE and malondialdehyde (MDA), are heightened in both the brain tissues of AD patients and corresponding animal models (Park et al., 2021).”
The emerging role of NADPH oxidases (NOX) in Alzheimer’s disease pathogenesis
Yadav, A., Verma, H., Kumari, S., Gangwar, P., Rao, R., Yadav, B., Kaur, S., Dhiman, M., & Mantha, A. K. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.08.004
Wang, Y., Wang, Y., Li, Q., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1854785
“…expressed in organs and catalyzes the conversion of molecular oxygen into superoxide anions ( • O 2 − ) and ROS (Ogboo et al., 2022; Lambeth et al., 2007), exerting a pivotal role in the modulation of oxidative stress and downstream signals (Liao et al., 2022; Wang et al., 2022; Park et al., 2021).”
Development of a first-in-class homolog-selective, covalent NOX4 inhibitor
Castelôa, M., Marchese, S., Massari, M., Lima, C., Basile, L., Reis, J., Ré, M., Martins, F. G., Sousa, S. F., Lima, I., et al. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119844
Wu, S., Zhang, X., Wei, S., Lu, M., Sun, L., & Wang, H. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.179255
Wang, Y., Hao, D., Fan, X.-Y., Pan, L.-M., Duan, H., Yan, J., Yao, Y., Zha, M., Sarun, P., Du, Y.-J., et al. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.179251
Salunkhe, J., & Ugale, V. G. (2026) · Drug Development Research · doi:10.1002/ddr.70367
“Elevated levels of 4‐hydroxynonenal (4‐HNE), a reactive aldehyde derived from lipid oxidation, and mal-ondialdehyde (MDA), another marker of oxidative stress, have been consistently detected in the brains of AD patients and APP/PS1 mouse models (Lovell et al. 1997; Park et al. 2021).”
Thakur, M., Mutyala, D., Amoliga, A., Ortega, M. C., & Batra, S. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01447-2
Liu, Y., Liu, Z., Xu, H., Zhou, Y., Chen, Y., Wang, L., Zhao, F., Gao, L., & Pan, T. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1912506
Maghareh, M., Carrera, E. M., Cicala, D. S., Roknuzzaman, A. S. M., Sarker, R., Geldenhuys, W. J., & Huber, J. D. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1838011
“…dysfunction, for example, using rotenone, exacerbates ferroptotic neuronal death, further supporting a mechanistic connection between mitochondrial impairment and ferroptosis in ICH (Ryan et al., 2023; Park et al., 2021; Liu et al., 2025; Li J. et al., 2022; Jacquemyn et al., 2024) (Figure 1).”
Wang, Y., Wu, W., Yan, L., Zhang, B., Li, Q., & Zhou, Y. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1849218
“Notably, oxidative stress and its synaptic biomarkers appear before the formation of A β plaques and neurofibrillary tangles (Park et al., 2021).”
Yi, Y., Chen, C., He, Y., Yu-zhou, S., Cheng, R., Liu, M., Liu, Z., & Zhang, X. (2026) · Medicinal Research Reviews · doi:10.1002/med.70103
Li, F., Song, J., Zou, W., et al. (2026) · Redox Report · doi:10.1080/13510002.2026.2724653
“This is further supported by evidence that both isoforms can drive ferroptosis [30,51–54].”
The role of oxidative stress in the pathogenesis of neuroinflammation
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Music intervention as a therapeutic approach to cognitive impairments in APP/PS1 mice
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Vorwald, M. E., Roths, M. S., Valentine, R. J., & Selsby, J. T. (2026) · Biomolecules · doi:10.3390/biom16091347
“NADPH oxidase 4 (NOX4) promotes ferroptosis by increasing ROS production [41].”
Mao, J., Zhang, Y., Wang, P., & Qin, D. (2026) · Cells · doi:10.3390/cells15191721
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“Oxidative stress further impairs mitochondrial membranes through triggering mitochondrial lipid peroxidation alongside the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) — molecules capable of inflicting additional harm on proteins, lipids, and mtDNA [107 – 109].”
Li, Y., Wang, J., Sun, H., & Fu, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1882853
Zheng, S., Zheng, S., Ji, X., et al. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1862317
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Metadata
- Authors
- Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S.
- Affiliations
- Soonchunhyang University (KR)
- Soonchunhyang University Hospital Cheonan (KR)
- Corresponding author
- Yoo, Ik Dong
- Moon, Jong-Seok
- ORCID
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 41
- Pages
- 101947
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC8027773
- OpenAlex
- W3136661179
- Cited by
- 683
- References
- 92
- Citations by year
- 2026: 139 · 2025: 145 · 2024: 187 · 2023: 128 · 2022: 74 · 2021: 10
- FWCI
- 62.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Soonchunhyang University
- National Research Foundation of Korea
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX4, ferroptosis, astrocytes, Alzheimer's disease, oxidative stress, lipid peroxidation, mitochondrial dysfunction, mitochondrial respiration, mitochondrial electron transport chain, mitochondrial reactive oxygen species, mitochondrial fragmentation, 4-hydroxynonenal, malondialdehyde, APP/PS1 mice, reactive oxygen species
- MeSH terms
- NADPH Oxidase 4, Ferroptosis, Alzheimer Disease, Animals, Astrocytes, Humans, Mitochondria, Lipid Peroxidation, Reactive Oxygen Species, Oxidative Stress, Mice
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