Oxidative stress causes mitochondrial dysfunction in obesity and type 2 diabetes mellitus (T2DM), but the molecular mechanisms underlying the cause remain poorly elucidated. Cardiolipin (CL) is a mitochondrial membrane phospholipid required for oxidative phosphorylation and mitochondrial biogenesis. The biological function of CL is determined by its acyl composition, which is dominated by linoleic acid in healthy metabolic tissues. In contrast, the onset of obesity and T2DM is associated with a significant alteration of acyl composition from the healthy tetralinoleoyl CL (TLCL) to the CL species enriched with docosahexaenoic acid (DHA) which is highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL functions as ROS, initiating a chain of events of oxidative stress and CL oxidation known as """"""""CL peroxidation."""""""" Research supported by this grant has identified a key role of ALCAT1, a lysocardiolipin acyltransferse, in mitochondrial dysfunction associated with obesity and T2DM by catalyzing the synthesis of CL with a high peroxidation index. The research has also shown that ALCAT1 expression is induced by ROS associated with obesity and T2DM, triggering a vicious cycle of oxidative stress, mitochondrial dysfunction, and insulin resistance. Consequently, we show that targeted deletion of ALCAT1 in mice ameliorates diet-induced obesity (DIO) and its related mitochondrial dysfunctions. Strikingly, our new preliminary data also reveal an unexpected role of ALCAT1 in regulating mitochondrial fusion and mtDNA fidelity through the modulation of mitofusin-2 (MFN2), a GTPase required for mitochondrial fusion, linking oxidative stress by ALCAT1 to defective mitochondrial quality control. Based on these new preliminary data, we hypothesize that CL remodeling by ALCAT1 causes mitochondrial dysfunction in DIO by impairing mitochondrial fusion, which will be tested by three specific aims:
Aim 1 will identify the role of CL remodeling by ALCAT1 in defective mitochondrial quality control in DIO;
Aim 2 will determine the role of MFN2 deficiency by ALCAT1 in mitochondrial dysfunction in DIO;
and Aim 3 will elucidate the molecular mechanism by which ALCAT1 regulates mitochondrial autophagy in DIO and T2DM. Successful completion of the proposed studies will open a new direction to study pathways that integrate CL remodeling to defective mitochondrial biogenesis and quality control in metabolic diseases. This information will have profound implications in designing new therapeutic strategies against obesity and other age-related diseases, because pathological CL remodeling is implicated in mitochondrial dysfunction associated with all the age-related diseases, including obesity, T2DM, cardiovascular diseases, cancer, and neurodegeneration.

Public Health Relevance

The work sponsored by this grant has identified a key role of ALCAT1, enzyme that catalyzes the synthesis of bad lipid, in mitochondrial dysfunction in diet-induced obesity and type 2 diabetes. This competitive renewal will allow us to identify molecular mechanisms by which ALCAT1 regulates mitochondrial dysfunction in metabolic diseases, thus providing key information on whether inhibition of ALCAT1 can provide a novel treatment of diabetes, obesity, and cardiovascular diseases.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Pawlyk, Aaron
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Pennsylvania State University
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Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Cao, Dongmei; Ma, Xianhua; Cai, Jiao et al. (2016) ZBTB20 is required for anterior pituitary development and lactotrope specification. Nat Commun 7:11121
Li, Ling; Gao, Lin; Wang, Kejia et al. (2016) Knockin of Cre Gene at Ins2 Locus Reveals No Cre Activity in Mouse Hypothalamic Neurons. Sci Rep 6:20438
Liu, Ying; Takahashi, Yoshinori; Desai, Neelam et al. (2016) Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin resistance. Sci Rep 6:20453
Chen, Fang; Sha, Min; Wang, Yanyang et al. (2016) Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models. Diabetologia 59:316-24
Hsu, Paul; Liu, Xiaolei; Zhang, Jun et al. (2015) Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy. Autophagy 11:643-52
Wang, Li; Liu, Xiaolei; Nie, Jia et al. (2015) ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology 61:486-96
Zhang, Jun; Xu, Dan; Nie, Jia et al. (2015) Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase. J Biol Chem 290:241
Zhou, Xiu; Xu, Jun; Shi, Yuguang et al. (2015) Discovery of Novel Anti-Diabetic Drugs by Targeting Lipid Metabolism. Curr Drug Targets 16:1372-80
Zhang, Jun; Xu, Dan; Nie, Jia et al. (2014) Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase. J Biol Chem 289:33044-53

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