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 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.
Pallast
Stefanie
S
Neuroprotection Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Arai
Ken
K
Wang
Xiaoying
X
Lo
Eng H
EH
van Leyen
Klaus
K
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000494:pharmacology*; D002999:Clone Cells; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005434:Flow Cytometry / Q000379:methods; D018698:Glutamic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000648:ultrastructure*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D016859:Lipoxygenase Inhibitors; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D045304:Cytochromes c; D001093:Arachidonate 15-Lipoxygenase; D005978:Glutathione