title: Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
abstract: Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1(-/-) mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Caroline
authors.initials: C
authors.lastname: Romestaing
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Xinbao
authors.initials: X
authors.lastname: Hao
authors.forename: Yinyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.forename: Jingwei
authors.initials: J
authors.lastname: Xiong
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Lanoue
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.forename: Huayan
authors.initials: H
authors.lastname: Wang
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D002460:Cell Line; D007333:Insulin Resistance; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002308:Cardiolipins; D017382:Reactive Oxygen Species; D000217:Acyltransferases; C525544:lysocardiolipin acyltransferase, mouse