Thursday, 15 October 2015

New compounds to directly modulate mitochondrial ROS

Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat
Ellen L. Robb, Justyna M. Gawel, Dunja Aksentijevińá, Helena M. Cochem√©,Tessa S. Stewart, Maria M. Shchepinova, He Qiang, Tracy A. Prime, Thomas P. Bright, Andrew M. James, Michael J. Shattock, Hans M. Senn, Richard C. Hartley, Michael P. Murphy

A mitochondria-targeted derivative of ascorbate: MitoC
Peter G. Finichiu, David S. Larsen, Cameron Evans, Lesley Larsen, Thomas P. Bright, Ellen L. Robb, Jan Trnka, Tracy A. Prime, Andrew M. James, Robin A.J. Smith, Michael P. Murphy

When mitochondria malfunction, the components of the electron transport chain may leak electrons and generate reactive oxygen species (ROS). The role of ROS in physiological and pathophysiological settings is subtle, as low levels are thought to be important in cell signalling whereas high levels may cause damage to a variety of biomolecules. In order to test the causal link between ROS and pathology, it is important to be able to directly modulate their levels and test their outcome.

In the above two papers, the Murphy group fuse a particular cation (triphenylphosphonium lipophilic cation, TPP), to two agents (paraquat and ascorbate, which are oxidizing and reducing agents repectively) allowing their localisation to the mitochondrial matrix. The resulting compounds are named MitoPQ and MitoC respectively. Once in the matrix, MitoPQ is able to generate ROS, whereas MitoC is able to mop ROS up. Importantly, this occurs at the site of ROS generation (the mitochondrial matrix). Many known agents can only modulate ROS in the cytosol, so these compounds provide more direct control over mitochondrial ROS. Furthermore, due to their direct localisation, lower concentrations of the compounds are required relative to their non-mitochondrial counterparts, to achieve the same effect.

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