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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

Final Activity Report Summary - IF1 AND CELL DEATH (Expression and function of the endogenous inhibitor of the mitochondrial F1F0-ATPase, IF-1, and its role during ischaemia)

Mitochondria are microscopic structures within cells that are essential for normal cell function. They house the machinery required to use oxygen and to create molecules that can be used to power energy dependent processes, such as muscle contraction, firing nerve impulses, secreting hormones etc. Indeed, the only reason we have to breathe oxygen is to provide our mitochondria with oxygen to carry out these fundamental reactions. Under conditions in which mitochondria do not have sufficient supply of oxygen, such as during episodes of hypoxia, during a stroke or a heart attack, mitochondrial reactions may reverse so that they use up the energy providing molecules rather than generate them. Cells make a protein that is thought to act as a brake to this mechanism, known as the endogenous inhibitor factor or IF-1.

As almost all information on this protein is based on biochemical experiments, and almost nothing is known about its behaviour within the cell, we have explored its actions in living cells. We have been able to manipulate the expression of the protein and using fluorescent indicators and fluorescence microscopy, have explored its impact both on normal mitochondrial function and on the response to hypoxia. We have established that the protein significantly protects cells from hypoxic injury and helps to preserve energy state of the cell.

We also had some surprising results that suggest that the protein is a profound modulator of normal mitochondrial function, increasing the numbers of mitochondria in cells, increasing the efficiency by which they make energy rich molecules and altering mitochondrial structure. This is the first time that there has been any suggestion that the protein has any role to play in normal mitochondrial function.

This leads to all sorts of interesting questions about the relative expression of the protein in different cell types and to further explorations of the role of the protein as a determinant of mitochondrial function. This is potentially very important, as mitochondria are different in different tissues; their efficiency, structure and density all vary, as does their vulnerability to injury. Understanding the factors that dictate these differences may help us to understand why some tissues are more vulnerable to hypoxic injury than others.