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Expression and function of the endogenous inhibitor of the mitochondrial F1F0-ATPase, IF-1, and its role in shaping the cellular response during ischaemia and cell death


ATP fuels all cellular processes and is fundamental for life and well-being. Mitochondria, which play a central role in cell regulation, are the principal source of cellular ATP. It is increasingly clear that defects in mitochondrial function underlie many major diseases (e.g. of the heart and central nervous system).

The ATP produced by mitochondria is synthesised by the F1-F0 ATP synthase. The enzyme is a proton motive ATPase, which is driven as an ATP synthase by the proton motive force, expressed primarily as a potential. If the potential collapses, e.g. under pathological conditions such as anoxia, the enzyme reverts from ATP synthesis to ATP hydrolysis, glycolysis becomes the only source of cellular ATP and mitochondria act as ATP consumers.

IF-1 is a protein, which inhibits ATPase activity. It binds the F1 sector of the ATPase, limits its hydrolytic activity and so protects the cell from ATP depletion. IF-1 is therefore a key determinant of cell survival during potentially lethal events such as ischemia, a major cause of death in industrialized countries. Furthermore, as the pathway of cell death to apoptosis or to necrotic cell death depends on ATP availability, IF-1 may play an important role in defining the pathway to cell death.

Remarkably, despite extensive and detailed knowledge IF-1 at a molecular level little is known about its comparative cell physiology between cell types and between species. The aim of my research training at the Physiology Department of the University College London is to characterize the functional contribution of IF-1 in physiological and pathological conditions.

Specifically, we plan
- to examine IF-1 expression and localization in different tissues and different species
- to use molecular biological techniques to generate recombinant probes of IF-1
- to examine the physiological and pathological consequences of alterations of IF-1 gene expression.
- Finally, to asses the role of IF-1 in cell death and tumourigenesis.

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