The role of the mitochondrial endogenous inhibitor, IF-1, in ischaemia and reperfusion injury in the heart. (360G-Wellcome-083763_Z_07_Z)

Mitochondrial dysfunction is central to the pathogenesis of a number of major diseases. At the heart of this proposal is the principle that a decreased mitochondrial membrane potential causes the mitochondrial ATP synthase to operate in 'reverse', switching mitochondria from ATP producers to consumers. The best characterized example of this mechanism is the response of cardiac muscle to ischaemic injury, in which mitochondrial dysfunction defines the borderline between reversible and irreversibl e injury. ATPase activity is modulated by the endogenous inhibitor protein, IF-1, which should be protective by conserving cellular ATP at the expense of allowing the potential to dissipate. As ATP depletion and changes in mitochondrial membrane potential play key roles in defining the progression of ischaemic injury, understanding the processes by which they are regulated is key to understanding the progression of ischaemic injury and so defining therapeutic targets. The proposed experimental w ork will therefore explore the impact of overexpression or suppression (siRNA) of IF-1 protein levels on the evolution of ischaemic injury in cardiac cells and cell lines. Mitochondrial state also defines the pathways of cell death, and so the work will also identify the impact of IF-1 on cell fate.