FAST BREAKING PAPERS

Why do you think your paper is highly cited?

Radical production and oxidative damage in mitochondria contribute to a range of important biomedical processes, including to the aetiology of a number of pathologies. Therefore there is considerable interest in methodologies that can selectively target mitochondrial oxidative damage and other malfunctions.

Does it describe a new discovery, methodology, or synthesis of knowledge?

It is really a new methodology, which involves the design, synthesis, and bioevaluation of composite chemicals that involve conjugation of lipophilic cations. These new chemicals include components which allow them to target mitochondria.

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

Mitochondria are one of the constituents of a cell and are central to how cells use energy. Mitochondrial malfunction is linked to various disease states and this approach enables us to monitor and selectively protect mitochondria from damage. This research has the potential to logically develop useful chemicals for treatment of diseases characterized by mitochondrial damage.

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

This work grew out of a multidisciplinary collaboration between a biochemist interested in probing and modifying mitochondria (Murphy) and a chemist with an interest in making bioactive molecules (Smith) while we were both employed at the University of Otago, New Zealand.

Where do you see your research leading in the future?

This approach has led to the development of a small-molecule pharmaceutical that is now in Phase II human clinical trials. In addition, this mode of targeting has also been used to develop probes of mitochondria function, such as MitoSOX™ (Molecular Probes®), and many more chemicals are under development to enable us to learn more about mitochondrial function.

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

Hopefully this work may contribute to addressing some of the diseases which feature mitochondrial malfunction in their aetiology.

Below are images sent in by Michael P. Murphy & Robin A. J. Smith which corresponds with the featured paper, or current research.
Figure 1: ¦enlarge image¦
	Oral uptake and distribution of a mitochondria-targeted antioxidant. An ideal mitochondria-targeted antioxidant would be orally bioavailable, being rapidly taken up into the blood stream from the gut. From there it would pass into cells within those tissues affected by mitochondrial damage, such as the heart, brain, liver and muscle. The antioxidant would then accumulate within mitochondria and protect them from oxidative damage. Ideally, the compound would be recycled back to its active antioxidant form after having detoxified the damaging reactive oxygen species (ROS). ¦enlarge image¦
Figure 2: ¦enlarge image¦
	Accumulation of MitoQ10 into cells and mitochondria. MitoQ10 will first pass through the plasma membrane and accumulate in the cytosol driven by the plasma membrane potential (Dyp). From there it will be further accumulated several-hundred fold into the mitochondria, driven by the mitochondrial membrane potential (Dym). There it will be reduced to the active antioxidant ubiquinol. In preventing oxidative damage it will be oxidised to the ubiquinone which will then be re-reduced. ¦enlarge image¦

Professor Robin A.J. Smith
Mellor Professor of Chemistry
Chemistry Department
University of Otago
Dunedin, New Zealand

Dr. Michael P. Murphy
Group Leader
Mitochondrial Dysfunction
MRC Dunn Human Nutrition Unit
Wellcome Trust/MRC Building
Cambridge, UK