Control of Mitochondrial Respiration & Oxidative Stress

Dana-Farber Cancer Inst, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): Mitochondrial respiration is a biochemical process that produces energy in form of ATP (coupled respiration) or heat (uncoupled respiration). A major consequence of this oxidative process is the formation of Reactive Oxygen Species (ROS) that will produce oxidative stress in cells and will result in cellular defects and tissue injury. The cellular levels of ROS will be determined by either the ability to degrade ROS through scanvenger enzymes or by preventing its formation by uncoupling respiration. In obesity and diabetes, hyperglycemia is a major cause of abnormalities in mitochondrial metabolism leading to an overproduction of ROS. Previous studies have shown that the transcriptional coactivator PGC-1alpha is a major regulator of mitochondrial function and oxidative stress. PGC-1alpha is deregulated in skeletal muscle of obese and diabetic patients. Our laboratory have recently found that the nutrient sensor mTOR, up-regulates PGC-1alpha and its targets genes. Paradoxically, in skeletal muscle mTOR pathway has been shown to be active in obesity and diabetes, while PGC-1alpha and mitochondrial genes are downregulated. We are proposing here to test the hypothesis that a disconnection between the mTOR and PGC-1alpha pathways are a major contribution to oxidative stress in diabetes and obesity. This application contains two Specific Aims. First, using genetic and cellular approaches we will perform a gene expression and functional analysis of mitochondrial respiration and ROS production controlled by mTOR activation through PGC-1alpha. Second, using genome-microarray, bioinformatics and biochemical approaches we will identify DNA promoter sequences and transcription factors targeted by the mTOR signaling that control PGC-1alpha gene expression. Taken together, the findings of these studies will allow us to identify novel molecular mechanisms by which the nutrient sensor mTOR and PGC-1alpha control mitochondrial respiration and production of ROS. Understanding why and how these two pathways are disconnected in obese and diabetes patients could be useful to develop therapies that can prevent ROS formation in these metabolic diseases.