Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

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Abstract Mitochondrial dysfunction is a common defect associated with obesity and its metabolic complications. Yet, the underlying causes of the dysfunction remain elusive. Our long term goal is to elucidate the regulatory mechanisms of cardiolipin (CL) remodeling in mitochondrial dysfunctions associated with diabetes, obesity, cardiovascular diseases, and aging. This project will address a hypothesis that ALCAT1 regulates mitochondrial activity and energy homeostasis by modulating linoleic acid content of cardiolipin in response to oxidative stress. This hypothesis is based on our preliminary results that 1) ALCAT1 is localized mitochondriaassociated membrane where it catalyzes reacylation of lysocardiolipin. 2) Overexpression of ALCAT1 in COS-7 cells improves mitochondrial function and prevents the COS-7 cells from damage by oxidative stress. 3) ALCAT1 enzyme activity and mRNA is up-regulated by diabetes and obesity that are associated with an increased level of oxidative stress and cardiolipin peroxidation. Treatment with rosiglitazone improves mitochondrial function and stimulates ALCAT1 expression and enzyme activity. 4) Transgenic mice deficient in ALCAT1 expression are resistant to diet-induced obesity concurrent with increased linoleic acid content in CL. Our hypothesis will be tested in three specific aims. 1. To determine the role of ALCAT1 in regulating mitochondrial function under oxidative stress. 2. To investigate how ALCAT1 deficiency affects energy homeostasis and metabolic complications. 3. To identify changes in cardiolipin and phospholipid profiles associated with ALCAT1 deficiency. Results from the current work is expected to identify molecular mechanisms underlying the regulatory role of ALCAT1 in mitochondrial dysfunction associated with diabetes and obesity, and to validate ALCAT1 as a drug target for metabolic diseases and aging.