Michael P. Murphy & Robin
A. J. Smith talk with ScienceWatch.com and answers
a few questions about this month's Fast Breaking Paper in
the field of Pharmacology & Toxicology.
Field: Pharmacology & Toxicology
Article Title: Targeting antioxidants to mitochondria by
conjugation to lipophilic cations
Journal: ANNU REV PHARMACOL TOXICOL
* MRC, Dunn Human Nutr Unit, Wellcome Trust MRC Bldg,
Cambridge CB2 2XY, England.
* MRC, Dunn Human Nutr Unit, Cambridge CB2 2XY,
(addresses may have been truncated; see full
Why do you think your paper is highly
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?
"...there is considerable
interest in methodologies that can selectively target
mitochondrial oxidative damage and other
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
Would you summarize the significance of your paper in
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
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
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
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.
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
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
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.
Professor Robin A.J. Smith
Mellor Professor of Chemistry
University of Otago
Dunedin, New Zealand
Dr. Michael P. Murphy
MRC Dunn Human Nutrition Unit
Wellcome Trust/MRC Building