Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
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.
Li
Jia
J
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Romestaing
Caroline
C
Han
Xianlin
X
Li
Yuan
Y
Hao
Xinbao
X
Wu
Yinyuan
Y
Sun
Chao
C
Liu
Xiaolei
X
Jefferson
Leonard S
LS
Xiong
Jingwei
J
Lanoue
Kathryn F
KF
Chang
Zhijie
Z
Lynch
Christopher J
CJ
Wang
Huayan
H
Shi
Yuguang
Y
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
D002308:Cardiolipins; D017382:Reactive Oxygen Species; D000217:Acyltransferases; C525544:lysocardiolipin acyltransferase, mouse