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Preventing cell death

Anti-apoptotic effect of carbon monoxide in astrocytes
Preventing cell death

Primary culture of astrocytes from cortex

Oeiras, 28.04.10

Researchers from the Animal Cell Technology Unit have unraveled the mechanism behind apoptosis prevention by carbon monoxide (CO) in astrocytes. The process involves the inhibition of mitochondrial membrane permeabilization, a key step in several cell death processes, like apoptosis and necrosis. Results were published in the Journal of Biological Chemistry.

While CO is known to play a role in apoptosis prevention, little is known about its effect in the central nervous system. In previous work, researchers showed that CO inhibits neuronal apoptosis by a preconditioning-like effect. Now, they demonstrated that CO prevents apoptosis in astrocytes by acting directly on mitochondria and inhibiting their membrane permeabilization.

The proposed biochemical mechanism involves reactive oxygen species and oxidized glutathione as signaling molecules; as well as glutathionylation (as post-translation modification) of adenine nucleotide translocase, an inner membrane protein involved in mitochondrial membrane permeabilization.

Behind preconditioning is the idea that a small stress prepares the tissue or organ for a larger stress and thus, paradoxically, has a protective role. This phenomenon is widely studied in the heart and has been exploited in heart attack prevention. Similarly, understanding preconditioning in brain cells could open new perspectives for preventing the effect of strokes.

This research “niche” at the ACT Unit, headed by Helena L.A. Vieira since 2007, has focused on new strategies to prevent cerebral damage due to hypoxia-ischemia and reperfusion (the major damage occurs when the blood circulation is restored after its interruption). Researchers, in collaboration with an Italian research group, are now testing their theories using an in vivo model of perinatal hypoxia-ischemia. The main goal of this work is to apply carbon monoxide to trigger preconditioning and to prevent neuronal and astrocytic cell death.


Original Article

J Biol Chem. 2010 Mar 26. [Epub ahead of print] doi: 10.1074/jbc.M109.06505  

Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilisation and apoptosis

Claudia S. F. Queiroga, Ana S. Almeida, Cecile Martel, Catherine Brenner, Paula M. Alves and Helena L. A. Vieira

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