TY - JOUR
T1 - Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity
AU - Li, Jia
AU - Romestaing, Caroline
AU - Han, Xianlin
AU - Li, Yuan
AU - Hao, Xinbao
AU - Wu, Yinyuan
AU - Sun, Chao
AU - Liu, Xiaolei
AU - Jefferson, Leonard S.
AU - Xiong, Jingwei
AU - Lanoue, Kathryn F.
AU - Chang, Zhijie
AU - Lynch, Christopher J.
AU - Wang, Huayan
AU - Shi, Yuguang
N1 - Funding Information:
We thank Xian Li for help with statistical analysis and Tomas Garner for critically reading the manuscript. This study was supported in part by grants from the NIH (DK076685, Y.S.; DK062880, C.J.L.; DK15658, L.S.J.; and P01 HL57278, X. Han), the Chinese National Natural Science Foundation (#30871786, H.W.), and a scholarship from the Chinese National Scholarship Council (J.L.).
PY - 2010/8/4
Y1 - 2010/8/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2010.07.003
DO - 10.1016/j.cmet.2010.07.003
M3 - Article
C2 - 20674860
AN - SCOPUS:78049407128
SN - 1550-4131
VL - 12
SP - 154
EP - 165
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -
