Oxidative stress: Mechanism of cell death clarified

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Oxidative stress: Mechanism of cell death clarified

http://www.eurekalert.org/pub_releases/2008-09/hzm--osm090308.php

Life processes in cells require a reducing environment that needs to

be sustained with the help of a large number of antioxidative

enzymes. This may sound abstract and incomprehensible, but everyone

knows the phenomenon that a piece of cut apple or a piece of cut meat

changes colour quickly and deteriorates, because the oxygen in the

air produces chemical reactions in the tissues (oxidation of

biomolecules).

If the equilibrium in the organism moves towards oxidative processes,

then this is known as oxidative stress. Oxidative stress, for

instance, is associated with the aging of body cells. Furthermore, a

strong accumulation of reactive oxygen species (ROS) along with drops

in cellular concentrations of glutathione, (GSH), the major

antioxidant produced by the body, is well known as a common cause of

acute and chronic degenerative diseases, such as, arteriosclerosis,

diabetes, stroke, Alzheimer's and Parkinson's diseases.

" To investigate the molecular function of the cellular reducing agent

GSH in the metabolic pathway of cell death triggered by oxidative

stress, mice and cells were generated that specifically lack

glutathione peroxidase 4 (GPx4), which is emerging as one of the most

important GSH dependent enzymes " , explains Marcus Conrad. The induced

inactivation of GPx4 caused massive oxidation of lipids and

eventually cell death. A similar phenotype could be observed when

intracellular GSH was removed from wild-type cells by a chemical

inhibitor of GSH biosynthesis.

Interestingly enough, this cell death could be completely prevented

by Vitamin E, but not by water-soluble antioxidants. Since the

oxidation of fatty acids in this cell death pathway, was of paramount

importance, multiple studies were performed to describe, in greater

detail, the source and nature of lipid peroxides.

Pharmacological and reverse genetic analyses showed that lipid

peroxides in GPx4-depleted cells do not appear by coincidence, but

accumulate due to increased activity of a specific enzyme of the

arachidonic acid metabolism, the 12/15-lipoxygenase. Activation of

apoptosis inducing factor (AIF), evidenced by its relocation from

mitochondria to the cell nucleus, was identified as another important

event in this signaling cascade.

The fact that oxidative stress is a major inducer of cell death is a

well accepted current model. Until now however, the source and nature

of the reactive oxygen species has remained obscure, as have

questions concerning the way they act. Marcus Conrad: " So far, it was

assumed that oxidative stress is detrimental to cells by unspecific

oxidation of many essential biomolecules, such as proteins and

lipids. That is why we were amazed to find that in cells lacking

either glutathione or glutathione peroxidase 4, a distinctive

signaling pathway is engaged, which causes cell death. The data

represent the first molecular analyses of a redox-regulated signaling

pathway, describing how oxidative stress is recognized in the body

and translated into cell death " .

Since this cell death cascade can be interrupted at any single stage

with the help of drugs, this pathway harbors promising targets for

therapeutic intervention to mitigate the deleterious effects of

oxidative stress in complex degenerative human diseases.