Reactive oxygen species shown essential for development of inner ear's balance machinery

Though linked to aging and cancer, reactive oxygen species plays another role

Reactive oxygen species (ROS) are normally produced as a product of metabolism, and, as their name implies, they are highly reactive with surrounding biological components. The ability of ROS to damage DNA and other critical molecules underlies their reputation for causing deleterious cellular effects and their association with aging, carcinogenesis, and atherosclerosis. However, in an unanticipated discovery suggesting that ROS may play important positive roles in development, researchers have found that the production of ROS by a particular enzyme is essential for inner ear development and for the ability to properly maintain balance.

The work is reported in Current Biology by a team of researchers, including Peter Kiss and Botond Banfi of the University of Iowa.

A biologically constructive function for ROS in development was unanticipated. Even a previously known beneficial role for ROS seems to be intimately linked to toxicity: White blood cells generate ROS by an NADPH oxidase enzyme to kill invading bacteria. In recent years, evidence has been accumulating that other NADPH oxidases, similar to that of white blood cells, are widespread in the body, but their function remains largely obscure.

In their study, the researchers show that a spontaneously discovered line of mutant mice, named "head slant" because of the odd head and body posture of these animals, carries a mutation in the Noxo1 gene, which encodes an NADPH oxidase enzyme. This error in Noxo1 inactivates the enzyme in the inner ear, leading to very specific consequences: Mutant mice lack the tiny calcium carbonate crystals of the inner ear, which, because of their large inert mass, normally enable animals to determine the direction of gravitational pull. The Noxo1 mutant mice are unable to sense gravity and therefore often fall, rest in a slanted posture, and are unable to remain on the surface of water. By inserting an intact Noxo1 gene into the genome of "head slant" mutants, researchers enabled the mutant mice to maintain balance. These findings indicate that reactive oxygen species produced at the right place at the right time can have a constructive developmental role, in contrast to their previously known toxic effects.

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Peter J. Kiss, Judit Knisz, Jonas Baltrusaitis, Curt D. Sigmund, and Botond Banfi of the University of Iowa in Iowa City, IA; Yuzhou Zhang and Richard J.H. Smith of University of Iowa Hospitals and Clinics in Iowa City, IA; Ruediger Thalmann of Washington University School of Medicine in St. Louis, MO; Elisabeth Verpy of Institut Pasteur in Paris, France. This work was supported by grants from the Roy J. and Lucille A. Carver College of Medicine and NSF (1-5198400).

Kiss et al.: "Inactivation of NADPH oxidase organizer 1 Results in Severe Imbalance." Current Biology 16, pages 208213, January 24, 2006 DOI 10.1016/j.cub.2005.12.025 www.current-biology.com


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