Several risks factors of the metabolic syndrome such as insulin resistance and obesity present mitochondrial dysfunction that is associated with increased intramyocellular lipid accumulation. In response to nutrients and cold stimuli, transcriptional complexes that contain PGC-1a control mitochondrial oxidative function to maintain energy homeostasis. mTOR is an important component that responds to nutrient and hormonal signals and regulates cell growth, size and survival. However, whether and how mTOR controls mitochondrial oxidative activities is unknown. We have preliminary experiments indicating that in skeletal muscle mTOR is necessary to maintain mitochondrial oxidative function. We have identified that the transcription factor YY1 and the coactivator PGC-1a are mediating mTOR mitochondrial effects through modulation of their physical interaction. However, the molecular mechanisms of the signal transduction from mTOR to YY1/PGC-1a are unknown. The major goal of this proposal is to identify the mechanisms by which mTOR pathway regulates mitochondrial gene expression through the YY1/PGC-1a and to test their functionality in in-vivo mouse models. To accomplish this goal, we will use a variety of biochemical, cellular and genetic approaches. We have three aims.
Aim 1 is to perform molecular and functional analysis of how mTOR controls YY1 transcriptional function.
Aim 2 is to carry out molecular and functional analysis of the mTOR activity-dependent interaction between YY1 and PGC-1a.
Aim 3 will determine the effects of mTOR inhibition on the metabolic and bioenergetic function in mice. This investigation will allow us to identify the molecular mechanisms by which the nutrient sensor pathway regulates YY1/PGC-1a and how defects in this pathway results in dysregulated mitochondrial function and energy balance.
Since mitochondrial pathways are dysregulated metabolic diseases such as obesity and type 2 diabetes, studies in this grant proposal to understand how mTOR control mitochondrial function might translate into potential therapies for these diseases.
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