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.

[1]  J. German,et al.  Docosahexaenoic acid accumulates in cardiolipin and enhances HT-29 cell oxidant production. , 1998, Journal of lipid research.

[2]  D. Wallace,et al.  Increased mitochondrial oxidative stress in the Sod2 (+/−) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Yuguang Shi,et al.  ALCAT1 is a polyglycerophospholipid acyltransferase potently regulated by adenine nucleotide and thyroid status. , 2009, American journal of physiology. Endocrinology and metabolism.

[4]  K. Nair,et al.  Effect of T(3)-induced hyperthyroidism on mitochondrial and cytoplasmic protein synthesis rates in oxidative and glycolytic tissues in rats. , 2007, American journal of physiology. Endocrinology and metabolism.

[5]  M. Lazar,et al.  Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. , 2004, The Journal of clinical investigation.

[6]  J. Lockwood,et al.  A Novel Cardiolipin-remodeling Pathway Revealed by a Gene Encoding an Endoplasmic Reticulum-associated Acyl-CoA:Lysocardiolipin Acyltransferase (ALCAT1) in Mouse* , 2004, Journal of Biological Chemistry.

[7]  R. Carroll,et al.  Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes. , 2002, Carcinogenesis.

[8]  Shuliang Chen,et al.  Loss of tafazzin in yeast leads to increased oxidative stress during respiratory growth , 2008, Molecular microbiology.

[9]  K. Petersen,et al.  Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. , 2004, The New England journal of medicine.

[10]  E. Lander,et al.  Reactive oxygen species have a causal role in multiple forms of insulin resistance , 2006, Nature.

[11]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[12]  Xiaohui Xie,et al.  Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Robert V Farese,et al.  The Endoplasmic Reticulum Enzyme DGAT2 Is Found in Mitochondria-associated Membranes and Has a Mitochondrial Targeting Signal That Promotes Its Association with Mitochondria* , 2009, Journal of Biological Chemistry.

[14]  Y. Asmann,et al.  Skeletal Muscle Mitochondrial Functions, Mitochondrial DNA Copy Numbers, and Gene Transcript Profiles in Type 2 Diabetic and Nondiabetic Subjects at Equal Levels of Low or High Insulin and Euglycemia , 2006, Diabetes.

[15]  J. Olefsky,et al.  Increased Malonyl-CoA Levels in Muscle From Obese and Type 2 Diabetic Subjects Lead to Decreased Fatty Acid Oxidation and Increased Lipogenesis; Thiazolidinedione Treatment Reverses These Defects , 2006, Diabetes.

[16]  Y. Asmann,et al.  Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association With Severe Insulin Resistance , 2008, Diabetes.

[17]  M. Schlame,et al.  Remodeling of Cardiolipin by Phospholipid Transacylation* , 2003, Journal of Biological Chemistry.

[18]  Olga Ilkayeva,et al.  Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. , 2008, Cell metabolism.

[19]  J. Cline,et al.  Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. , 2005, Gastroenterology.

[20]  Xianlin Han,et al.  Shotgun lipidomics of cardiolipin molecular species in lipid extracts of biological samples Published, JLR Papers in Press, January 31, 2006. , 2006, Journal of Lipid Research.

[21]  Qing Zhao,et al.  Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors , 2005, Nature chemical biology.

[22]  L. Heilbronn,et al.  Is mitochondrial dysfunction a cause of insulin resistance? , 2008, Trends in Endocrinology & Metabolism.

[23]  E. Benjamin,et al.  Association of Oxidative Stress, Insulin Resistance, and Diabetes Risk Phenotypes , 2007, Diabetes Care.

[24]  H. Motoshima,et al.  The NAD(P)H Oxidase Homolog Nox4 Modulates Insulin-Stimulated Generation of H2O2 and Plays an Integral Role in Insulin Signal Transduction , 2004, Molecular and Cellular Biology.

[25]  R. Wanders,et al.  Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. , 2003, The Journal of pediatrics.

[26]  P. Neufer,et al.  Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. , 2009, The Journal of clinical investigation.

[27]  G. Johnson,et al.  Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells , 2008, Journal of Biological Chemistry.

[28]  M. L. Greenberg,et al.  The biosynthesis and functional role of cardiolipin. , 2000, Progress in lipid research.

[29]  S. Olusi.  Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans , 2002, International Journal of Obesity.

[30]  H. Abboud,et al.  Subcellular localization of Nox4 and regulation in diabetes , 2009, Proceedings of the National Academy of Sciences.

[31]  M. Wajner,et al.  Long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies induce oxidative stress in rat brain , 2010, Neurochemistry International.

[32]  Xiaohui S. Xie,et al.  Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle , 2004 .

[33]  M. Portero-Otín,et al.  Influence of hyper‐ and hypothyroidism on lipid peroxidation, unsaturation of phospholipids, glutathione system and oxidative damage to nuclear and mitochondrial DNA in mice skeletal muscle , 2001, Molecular and Cellular Biochemistry.

[34]  A. Koller,et al.  PPARγ activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes , 2004 .

[35]  K. Petersen,et al.  Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Parents , 2005, PLoS medicine.

[36]  K. Feingold,et al.  Phospholipid scramblase-3 regulates cardiolipin de novo biosynthesis and its resynthesis in growing HeLa cells. , 2007, The Biochemical journal.

[37]  M. L. Greenberg,et al.  Absence of Cardiolipin in the crd1 Null Mutant Results in Decreased Mitochondrial Membrane Potential and Reduced Mitochondrial Function* , 2000, The Journal of Biological Chemistry.

[38]  P. Bénit,et al.  Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes , 2007, Cell.

[39]  J Bruce German,et al.  Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. , 2002, Journal of lipid research.

[40]  G. Hatch,et al.  Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)* , 2009, The Journal of Biological Chemistry.

[41]  Xiaoming Sheng,et al.  Mitochondrial Energetics in the Heart in Obesity-Related Diabetes , 2007, Diabetes.

[42]  Xianlin Han,et al.  Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction. , 2005, Biochemistry.

[43]  B. Morio,et al.  Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. , 2008, The Journal of clinical investigation.

[44]  W. M. Foster,et al.  NAD(P)H quinone oxidoreductase 1 is essential for ozone-induced oxidative stress in mice and humans. , 2009, American journal of respiratory cell and molecular biology.

[45]  G. Paradies,et al.  Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage. , 2002, Gene.

[46]  J. Leszyk,et al.  Mitochondrial Biogenesis and Remodeling during Adipogenesis and in Response to the Insulin Sensitizer Rosiglitazone , 2003, Molecular and Cellular Biology.

[47]  A. Rudich,et al.  Oxidative Stress Disrupts Insulin-induced Cellular Redistribution of Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase in 3T3-L1 Adipocytes , 1999, The Journal of Biological Chemistry.

[48]  G. Hatch,et al.  Purification and Characterization of Monolysocardiolipin Acyltransferase from Pig Liver Mitochondria* , 2003, The Journal of Biological Chemistry.

[49]  E. Lesnefsky,et al.  Cardiolipin Remodeling in the Heart , 2009, Journal of cardiovascular pharmacology.

[50]  R. Murphy,et al.  Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure Published, JLR Papers in Press, April 10, 2007. , 2007, Journal of Lipid Research.

[51]  B. Lowell,et al.  Mitochondrial Dysfunction and Type 2 Diabetes , 2005, Science.

[52]  G. Paradies,et al.  Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart: Involvement of Reactive Oxygen Species and Cardiolipin , 2004, Circulation research.

[53]  J. Lupton,et al.  The role of docosahexaenoic acid in mediating mitochondrial membrane lipid oxidation and apoptosis in colonocytes. , 2005, Carcinogenesis.

[54]  A. Koller,et al.  PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. , 2004, American journal of physiology. Heart and circulatory physiology.

[55]  Xianlin Han,et al.  Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study. , 2007, Biochemistry.

[56]  J. Bruce German,et al.  Lipid metabolome-wide effects of the PPARγ agonist rosiglitazones⃞s The online version of this article (available at http://www.jlr.org) contains an additional 4 tables. Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200169-JLR200 , 2002, Journal of Lipid Research.

[57]  D. Vance,et al.  Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: relation to dysregulated phosphatidylcholine metabolism. , 2006, Vascular pharmacology.

[58]  G. Sparagna,et al.  Role of cardiolipin alterations in mitochondrial dysfunction and disease. , 2007, American journal of physiology. Cell physiology.