The mitochondrial NADH oxidase Apoptosis Inducing Factor (AIF) is a well-defined mediator of cell death that also plays a critical role in maintainin normal mitochondrial function. While the mechanisms by which AIF regulates activity of mitochondria are poorly defined, a critical role for AIF has been demonstrated by a series of in vivo studies, using both mouse models and human patient tissues, which indicate a spectrum of mitochondrial abnormalities with clinical manifestations when AIF activity is lost. We have previously shown that AIF expression is increased in human prostate cancer, and defined a critical role for AIF in support of mitochondrial metabolism vital to the survival and growth of advanced prostate cancer cells. In preliminary studies we used a proteomics-based screen to identify novel AIF binding partners, and have validated factors associated with control of mitochondrial gene expression and cellular redox balance as targets of AIF activity. Our overall hypothesis is that AIF controls mitochondrial biogenesis and cellular redox balance by multiple mechanisms, and that this control supports metabolism necessary for the survival and growth of prostate cancer cells.
In Aim 1 we will define the specific means through which AIF controls mitochondrial biogenesis.
Aim 2 will determine the mechanisms employed by AIF to sense and respond to altered cellular redox levels. Finally, Aim 3 will employ a developmental model of prostate cancer progression to delineate the specific phases of prostate tumorigenesis at which AIF activity becomes necessary, and the initiating factors most dependent upon AIF for activity. Overall these studies will define the complete mechanistic program through which AIF achieves control of mitochondrial biogenesis and cellular redox balance, and the influence of these mechanisms upon prostate cancer and other diseases that are linked to AIF activity.
Apoptosis Inducing Factor (AIF) is a multifunctional protein that can control cell metabolism. We have found new ways for in which AIF may function, and this appears to be important for the survival of prostate cancer cells. This project will test new ideas about how AIF controls cell survival with the long term goal of developing new approaches to prostate cancer therapy.
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