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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
- Source :
- Redox Biology, Vol 41, Iss, Pp 101947-(2021), Redox Biology
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- 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.<br />Highlights • The levels of NOX4 were elevated in impaired astrocytes of human and mouse AD. • The levels of 4-HNE and MDA were elevated in impaired astrocytes of human and mouse AD. • NOX4 induces oxidative stress by the impairment of mitochondria in human astrocytes. • NOX4 promotes ferroptosis by oxidative stress in human astrocytes.
- Subjects :
- 0301 basic medicine
Mitochondrial ROS
Medicine (General)
QH301-705.5
Clinical Biochemistry
Oxidative phosphorylation
medicine.disease_cause
Biochemistry
Lipid peroxidation
NOX4
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
R5-920
Alzheimer Disease
medicine
Animals
Humans
Ferroptosis
Biology (General)
chemistry.chemical_classification
Reactive oxygen species
NADPH oxidase
biology
Organic Chemistry
Neurotoxicity
Alzheimer's disease
Malondialdehyde
medicine.disease
Cell biology
Mitochondria
030104 developmental biology
chemistry
NADPH Oxidase 4
Mitochondrial metabolism
Oxidative stress
Astrocytes
biology.protein
cardiovascular system
Lipid Peroxidation
Reactive Oxygen Species
030217 neurology & neurosurgery
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....fc7073026f22d21b7bc60c2c5cc752a6