12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress

12/15-Lipoxygenase (12/15-LOX) is an important mediator of brain injury following experimental stroke in rodents. It contributes to neuronal death, but the underlying mechanism remains unclear. We demonstrate here that in neuronal HT22 cells subjected to glutamate-induced oxidative stress, 12/15-LOX...

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Bibliographic Details
Published in:Journal of neurochemistry 2009-11, Vol.111 (3), p.882-889
Main Authors: Pallast, Stefanie, Arai, Ken, Wang, Xiaoying, Lo, Eng H, van Leyen, Klaus
Format: Article
Language:English
Subjects:
Ageing, cell death
Animals
Arachidonate 15-Lipoxygenase - pharmacology
Biochemistry
Biological and medical sciences
Brain damage
Cell physiology
Clone Cells
cytochrome c
Cytochromes c - metabolism
Endoplasmic Reticulum - drug effects
Flow Cytometry - methods
Fundamental and applied biological sciences. Psychology
Glutamic Acid - pharmacology
glutathione
Glutathione - metabolism
Hippocampus - cytology
lipoxygenase
Lipoxygenase Inhibitors - pharmacology
Medical sciences
Membrane Potential, Mitochondrial - drug effects
Mice
Mitochondria
Mitochondria - drug effects
Molecular and cellular biology
Neurology
Neurons - ultrastructure
Oxidation
Oxidative Stress - physiology
reactive oxygen species
Reactive Oxygen Species - metabolism
Rodents
Vascular diseases and vascular malformations of the nervous system
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Description
Summary:12/15-Lipoxygenase (12/15-LOX) is an important mediator of brain injury following experimental stroke in rodents. It contributes to neuronal death, but the underlying mechanism remains unclear. We demonstrate here that in neuronal HT22 cells subjected to glutamate-induced oxidative stress, 12/15-LOX damages mitochondria, and this represents the committed step that condemns the cell to die. Importantly these events, including breakdown of the mitochondrial membrane potential, the production of reactive oxygen species, and cytochrome c release, can all be replicated by incubation of 12/15-LOX with mitochondria in vitro, without the need to add other cytosolic factors. Proteasome activity is required downstream of mitochondrial damage to complete the cell death cascade, but proteasome inhibition is only partially protective. These findings position 12/15-LOX as the central executioner in an oxidative stress-related neuronal death program.
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2009.06379.x