Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

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DESCRIPTION (provided by applicant): The long term goal is to elucidate the molecular mechanisms by which defective cardiolipin (CL) metabolism contributes to the onset of mitochondrial dysfunction and metabolic diseases from oxidative stress. CL is a key mitochondrial phospholipid required for mitochondrial oxidative phosphorylation and ATP synthesis. Like cholesterols, there are "good" and "bad" CL, which is determined by the content of linoleic acid. The side chains of a good CL are dominated by linoleic acid, and a bad CL is enriched with long chain polyunsaturated fatty acids. The ratio of good vs. bad CL is modulated by a "remodeling" process that involves deacylation by phospholipases and reacylation by lysocardiolipin acyltransferases. Defective CL remodeling in response to reactive oxygen species (ROS) leads to accumulation of bad CL and mitochondrial dysfunction which have recently been identified as common defects in metabolic diseases including diabetes, obesity, cardiovascular diseases, and aging. We have recently cloned the first acyltransferase (ALCAT1) involved in defective CL remodeling. Our preliminary data demonstrate that ALCAT1 plays a causative role in mitochondrial dysfunction and insulin resistance in response to ROS. This project is test the hypothesis that defective CL remodeling by ALCAT1 in response to oxidative stress causes mitochondrial dysfunction and exacerbates metabolic complications in diet-induced obesity. The proposal will be accomplished by three Aims: 1) To identify molecular defects in mitochondrial dysfunction and insulin resistance caused by ALCAT1 overexpression in C2C12 or L6 stable cell lines; 2) To assess the physiological effects of ALCAT1 deficiency in mice on metabolic complications associated with diet-induced obesity; and 3) To determine the regulatory role of ALCAT1 in CL remodeling and phospholipid metabolism. Results from the current work are anticipated to fill in a missing link between mitochondrial dysfunction from oxidative stress and onset of metabolic complications associated with obesity. The proposed work will also help to validate ALCAT1 as a novel drug target for diabetes and obesity, and thereby stimulates pharmaceutical industry interests in development of novel treatment for metabolic diseases. PUBLIC HEALTH RELEVANCE: The proposed work will help to identify underlying causes of metabolic complications associated with obesity, such as diabetes and cardiovascular diseases. The results from the proposed research are anticipated to provide key information on whether inhibition of a key enzyme involved in synthesis of a bad lipid can provide a novel treatment of diabetes, obesity, and cardiovascular diseases.