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EMERGING RESEARCH FRONTS - 2008

Martin Brand talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front in the field of Biology & Biochemistry.
Brand Article: Superoxide activates mitochondrial uncoupling proteins
Authors: Echtay, KS;Roussel, D;St-Pierre, J;Jekabsons, MB;Cadenas, S;Stuart, JA;Harper, JA;Roebuck, SJ;Morrison, A;Pickering, S;Clapham, JC;Brand, MD
Journal: NATURE, 415 (6867): 96-99 JAN 3 2002
Addresses: MRC, Dunn Human Nutr Unit, Hills Rd, Cambridge CB2 2XY, England.
MRC, Dunn Human Nutr Unit, Cambridge CB2 2XY, England.
GlaxoSmithKline, Dept Comparat Genome, Harlow CM19 5AW, Essex, England.
GlaxoSmithKline, Dept Vasc Biol, Harlow CM19 5AW, Essex, England.

Why do you think your paper is highly cited?

This was the first report that directly connected an uncoupling function of mitochondrial uncoupling proteins to activation by reactive oxygen species (specifically, superoxide). It opened up a mechanistic link that also suggested physiological function, and so had an impact on two fields: uncoupling proteins and their putative roles in energy dissipation, obesity, and regulation of insulin secretion; and regulation of mitochondrial radical production, aging, and degenerative diseases. The new experimental discovery was that reactive oxygen species regulate the uncoupling function of UCPs (uncoupling proteins).

Would you summarize the significance of your paper in layman’s terms?

The brown adipose uncoupling protein (UCP1) is known to increase the dissipation of energy in cells, so in principle UCPs can cause calories to be burned, producing heat, rather than being laid down as fat. The novel UCPs (UCP2 and UCP3), which are present at low levels in many tissues, such as muscle, may or may not have the same function.

This paper showed firstly that UCP2 and UCP3, when assayed under suitable conditions, do indeed have the same uncoupling ability as UCP1, increasing the chances that they can be targeted pharmacologically to dissipate energy in muscle and elsewhere, and perhaps treat obesity and its associated conditions, such as diabetes.

Secondly, it showed that the UCPs only carried out this function when they were activated by reactive oxygen species (ROS). This was a surprise, as direct activation of uncoupling function by ROS was not previously suspected.

This opened up three areas: a way to activate the proteins that might be exploitable pharmacologically; the idea that UCPs may be involved in protection against free radical damage, and so target for affecting ageing and the diseases of ageing, which may be caused or exacerbated by mitochondrial ROS production; and the possibility that ROS activation of UCPs might be part of a signalling pathway, subsequently shown to be true for glucose-stimulated insulin secretion in pancreatic beta cells, and so a potential target for anti-diabetes drugs.

How did you become involved in this research and were any particular problems encountered along the way?

We were interested in mechanisms of uncoupling, and when Dr. Karim S. Echtay (the first author on the paper) joined the lab, we decided to follow up an earlier observation by him that ubiquinone could activate UCPs in vitro. We decided to look for such activation in intact mitochondria, and in the process discovered the activation by ROS. Once the question was posed, it was relatively straightforward to characterize the effects.

Where do you see your research leading in the future?

We and others are still working out the mechanism and physiological significance of ROS activation of UCPs, and the relationships between ROS production by mitochondria, uncoupling, and ageing.

Do you foresee any social or political implications for your research?

The research opened up new potential targets for the treatment of some of the major diseases of our time: obesity, diabetes, and ageing-related degeneration.

Martin Brand
Professor of Cellular Bioenergetics
MRC Dunn Human Nutrition Unit
Cambridge, UK

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2008 : April 2008 : Martin Brand