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Séminaire - Mike MurphyMitochondrial superoxide production in ischaemia-reperfusion injury

Abstract :

Mitochondrial ROS have long been known to contribute to ischaemia-reperfusion (IR)  injury in heart attack and stroke, but methods to stop this ROS production were limited. Over the past few years we have developed a mitochondria-targeted S-nitrosating agent, called MitoSNO, that we showed was effective in preventing ROS formation in IR injury with therapeutic implications. In addition, the protection by this compound suggested that ROS production in IR injury was mainly coming from complex I.
This led us to investigate the mechanism of the ROS production and using a metabolomic approach we found that the ROS production in IR injury  came from the accumulation of citric acid cycle substrates during ischaemia that then drove mitochondrial ROS production by reverse electron transport at complex I during reperfusion.
This surprising mechanism led up to develop further new therapeutic approaches.

Selected publications

A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury Edward T. Chouchani, Victoria R. Pell, Andrew  M. James, Lorraine M. Work, Kourosh Saeb-Parsy, Christian Frezza, Thomas Krieg and Michael P. Murphy. Cell Metabolism (2016) 23 254-263

Assessing the mitochondrial membrane potential in cells and in vivo using targeted click chemistry and mass spectrometry Angela Logan, Victoria R. Pell, Karl J. Shaffer, Cameron Evans, Nathan J. Stanley, Ellen L. Robb, Tracy A. Prime, Edward T. Chouchani, Helena M. Cochemé, Ian M. Fearnley, Sara Vidoni, Andrew M. James, Carolyn M. Porteous, Linda Partridge, Thomas Krieg, Robin A. J. Smith and Michael P. Murphy Cell Metabolism (2016) 23 379-386

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS Edward T. Chouchani, Thomas Krieg and Michael P. Murphy Nature (2014) 515 431-435

Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I Edward T. Chouchani, Carmen Methner, Sergiy M. Nadtochiy, Angela Logan, Victoria R. Pell, Shujing Ding, Andrew M. James, Helena M. Cochemé, Johannes Reinhold, Kathryn S. Lilley, Linda Partridge, Ian M. Fearnley, Alan J. Robinson, Richard C. Hartley, Robin A.J. Smith, Thomas Krieg, Paul S. Brookes and Michael P. Murphy Nature Medicine (2013) 19 753-759