Reduced expression of the ferroptosis inhibitor glutathione peroxidase‐4 in multiple sclerosis and experimental autoimmune encephalomyelitis

Glutathione peroxidase 4 (GPx4) is the only enzyme capable of reducing toxic lipid hydroperoxides in biological membranes to the corresponding alcohols using glutathione as the electron donor. GPx4 is the major inhibitor of ferroptosis, a non‐apoptotic and iron‐dependent programmed cell death pathwa...

Full description

Saved in:
Bibliographic Details
Published in:Journal of neurochemistry 2019-02, Vol.148 (3), p.426-439
Main Authors: Hu, Che‐Lin, Nydes, Mara, Shanley, Kara L., Morales Pantoja, Itzy E., Howard, Tamara A., Bizzozero, Oscar A.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alcohols
Animals
Apoptosis
Astrocytes
Biological membranes
Brain - enzymology
Brain - pathology
Cell Death
Cristae
Demyelination
Disorders
Docosahexaenoic acid
Encephalomyelitis, Autoimmune, Experimental - enzymology
Encephalomyelitis, Autoimmune, Experimental - pathology
Experimental allergic encephalomyelitis
experimental autoimmune encephalomyelitis
Female
Ferroptosis
Gene expression
Glutathione
Glutathione peroxidase
Glutathione Peroxidase - metabolism
glutathione peroxidase 4
Humans
Immunomodulation
Inhibitors
Iron
Isoenzymes - metabolism
Isoforms
Lipid peroxidation
Lipids
Male
Membranes
Mice
Mice, Inbred C57BL
Microglia
Middle Aged
Mitochondria
Mitochondria - enzymology
Mitochondria - pathology
mitochondrial damage
Modulators
Morphology
Multiple sclerosis
Multiple Sclerosis - enzymology
Multiple Sclerosis - pathology
Myelin
Neurological diseases
Neuromodulation
Oxidative stress
Peroxidase
Peroxidation
Phospholipid Hydroperoxide Glutathione Peroxidase
Proteins
Spinal cord
Spinal Cord - enzymology
Spinal Cord - pathology
Substantia grisea
γ-Glutamylcysteine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Glutathione peroxidase 4 (GPx4) is the only enzyme capable of reducing toxic lipid hydroperoxides in biological membranes to the corresponding alcohols using glutathione as the electron donor. GPx4 is the major inhibitor of ferroptosis, a non‐apoptotic and iron‐dependent programmed cell death pathway, which has been shown to occur in various neurological disorders with severe oxidative stress. In this study, we investigate whether GPx4 expression is altered in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). The results clearly show that mRNA expression for all three GPx4 isoforms (cytoplasmic, mitochondrial and nuclear) decline in multiple sclerosis gray matter and in the spinal cord of MOG35–55 peptide‐induced EAE. The amount of GPx4 protein is also reduced in EAE, albeit not in all cells. Neuronal GPx4 immunostaining, mostly cytoplasmic, is lower in EAE spinal cords than in control spinal cords, while oligodendrocyte GPx4 immunostaining, mainly nuclear, is unaltered. Neither control nor EAE astrocytes and microglia cells show GPx4 labeling. In addition to GPx4, two other negative modulators of ferroptosis (γ‐glutamylcysteine ligase and cysteine/glutamate antiporter), which are critical to maintain physiological levels of glutathione, are diminished in EAE. The decrease in the ability to eliminate hydroperoxides was also evidenced by the accumulation of lipid peroxidation products and the reduction in the proportion of the docosahexaenoic acid in non‐myelin lipids. These findings, along with presence of abnormal neuronal mitochondria morphology, which includes an irregular matrix, disrupted outer membrane and reduced/absent cristae, are consistent with the occurrence of ferroptotic damage in inflammatory demyelinating disorders. The anti‐ferroptosis enzyme GPx4 is critical for the elimination of toxic lipid hydroperoxides (LOOH) that arise from iron‐catalyzed oxidation of polyunsaturated fatty acids (PUFA). Here, we show that GPx4 mRNA and protein expression are reduced in spinal cord neurons of EAE mice. The accumulation of lipid hydroperoxides (LOOH) in experimental autoimmune encephalomyelitis (EAE) spinal cord, demonstrated by the rise in lipid peroxidation products and the decrease in PUFA levels, correlates with the appearance of additional ferroptosis markers such as characteristic damage to mitochondria. These findings provide the basis for the potential use of ferroptosis inhibitors or GPx4 inducer/activat
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.14604