The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids

Zhao, Yang; Chen, Yanqun; Li, Shuyu; Konrad, Robert J.; Cao, Guoqing

doi:10.1194/jlr.m800567-jlr200

Cited by 50 publications

(45 citation statements)

References 27 publications

(49 reference statements)

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“…The enzyme activity utilized both MLCL and dilysocardiolipin substrates and exhibited specificity for unsaturated long chain fatty acyl-CoAs. In addition, this enzyme catalyzed the acylation of a host of monoionic lysophospholipids (32,33). This enzyme is likely identical to the acyltransferase first described in rat liver ER (22).…”

Section: Discussionsupporting

confidence: 59%

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Taylor

Hatch

2009

Journal of Biological Chemistry

100

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Here we report the identification of a previously uncharacterized human protein as the human monolysocardiolipin acyltransferase-1 (MLCL AT-1). Pig liver mitochondria were treated with n-butyl alcohol followed by Q-Sepharose chromatography, preparative gel electrophoresis, cytidine diphosphate-1,2-diacyl-sn-glycerol-Sepharose chromatography, and finally monolysocardiolipin-adriamycin-agarose affinity chromatography. Elution with either monolysocardiolipin or linoleoyl coenzyme A revealed a major band at 74 kDa with high specific activity (2,300 pmol/min/mg) for the acylation of monolysocardiolipin to cardiolipin using Cardiolipin (CL)2 is a major phospholipid found in mammalian mitochondria with a multitude of biological functions (reviewed in Refs. 1-7). For example, CL is responsible for modulation of the activity of several mitochondrial enzymes involved in the generation of ATP (reviewed in Refs. 8, 9). In fact, it has been suggested that CL is the "glue" that holds the mitochondrial respiratory complex together (10). The role of CL in genetic diseases such as Barth syndrome, a rare X-linked genetic disorder, is beginning to emerge. Barth syndrome is the only known genetic disease in which the specific biochemical defect is a reduction in CL and accumulation of monolysocardiolipin (MLCL) caused by mutations in the TAZ gene (reviewed in Refs. 2,7,11,12). In addition, the role that CL plays in apoptosis is now well documented (reviewed in Ref. 13). Thus, maintenance of the appropriate content and fatty acyl composition of CL in mitochondria is essential for proper cellular function.The molecular composition of CL appears to be important for the biological function of CL. In general, there is a selection of a particular kind of fatty acid as well as restriction of the number of fatty acid species (14). The major tetra-acyl molecular species found in rat liver (ϳ57% of total) and bovine heart (ϳ48% of total) are 18:2 in each of the four fatty acyl positions of the cardiolipin molecule. Remodeling of CL is essential to obtain this enrichment of CL with linoleate because CL synthase has no molecular species substrate specificity for cytidine-5Ј-diphosphate-1,2-diacyl-sn-glycerol (15). In addition, the species pattern of CL precursors is similar enough to imply that the enzymes of the CL synthetic pathway are not molecular species-selective (16). Alterations in the molecular composition of CL are associated with various disease states, including diabetes and Barth syndrome (17,18

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Section: Discussionsupporting

confidence: 59%

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Taylor

Hatch

2009

Journal of Biological Chemistry

100

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“…Mammalian LYCAT is reported to possess acyltransferase activity toward the sn -2 position of anionic lysophospholipids including lysoPI, lysoPG, and lysoCL in vitro (17)(18)(19)(20). In this study, we examined the fatty acid composition of each phospholipid from various tissues of LYCAT Ϫ / Ϫ mice, and showed that LYCAT determines the fatty acid composition of PI in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…These results indicate that LYCAT signifi cantly contributes to acyltransferase activity toward the sn -1 position of PI and PG in mouse liver. Furthermore, sn -1-acyl LPIAT activity was reduced by 33% (from 0.15 ± 0.00 to 0.10 ± 0.00 nmol/min/mg protein) and LPGAT activity was reduced by 57% (from ferase activities toward the sn -2 position of PI and PG ( 20 ). sn -1-acyl LPCAT, LPEAT, and LPSAT activities were not altered signifi cantly in the LYCAT Ϫ / Ϫ liver ( Table 1 ).…”

Section: Lycat Defi Ciency Causes Reduced Acyltransferase Activity Tomentioning

confidence: 93%

“…sn -2-acyl lysophospholipid present in the lower layer was extracted by the method of Bligh and Dyer ( 22 ) and further purifi ed by TLC on silica gel 60 plates (Merck Biosciences, Darmstadt, Germany) in chloroform-methanol-acetic acid (65:25:13, v/v). The area of silica gel corresponding to sn -2-acyl lysoPI, and lysophosphatidylglycerol (lysoPG) in addition to lysoCL in vitro (18)(19)(20). Because C. elegans homologs of LYCAT specifi cally determines the fatty acyl chain at the sn -1 position of PI in vivo ( 12 ), here we examined if LYCAT determines the fatty acid composition of PI in mammals.…”

Section: Preparation Of Sn-2-acyl Lysophospholipidsmentioning

confidence: 99%

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LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

Imae

Inoué

Nakasaki

et al. 2012

Journal of Lipid Research

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Phosphatidylinositol (PI) is a relatively minor component of membrane phospholipids but plays important roles in signal transduction through distinct phosphorylated derivatives of the inositol head group ( 1, 2 ). Threefourths or more of membrane PI obtained from mammalian tissues consist of the 1-stearoyl-2-arachidonoyl (18:0/20:4) species ( 3, 4 ), which is thought to be formed by a fatty acid remodeling reaction after the de novo synthesis of PI ( 5-10 ). The remodeling reaction involves the hydrolysis of a fatty acyl ester bond at the sn -1 or sn -2 position of the newly synthesized PI and subsequent incorporation of the appropriate fatty acid into the position. In an RNA interference (RNAi)-based genetic screen using Caenorhabditis elegans , we identifi ed mboa-7/ LPIAT1 as an acyltransferase that selectively incorporates arachidonic acid into the sn-2 position of PI ( 11 ). More recently, we demonstrated that C. elegans acl-8 , acl-9 , and acl-10 , which show signifi cant sequence homology to each other, encode acyltransferases that incorporate stearic acid (18:0) into the sn-1 position of PI ( 12 ). Stearic acid attached at the sn -1 position of PI Abstract Mammalian phosphatidylinositol (PI) has a unique fatty acid composition in that 1-stearoyl-2-arachidonoyl species is predominant. This fatty acid composition is formed through fatty acid remodeling by sequential deacylation and reacylation. We recently identifi ed three Caenorhabditis elegans acyltransferases (ACL-8, ACL-9, and ACL-10 ) that incorporate stearic acid into the sn-1 position of PI. Mammalian LYCAT, which is the closest homolog of ACL-8, ACL-9, and ACL-10, was originally identifi ed as a lysocardiolipin acyltransferase by an in vitro assay and was subsequently reported to possess acyltransferase activity toward various anionic lysophospholipids. However, the in vivo role of mammalian LYCAT in phospholipid fatty acid metabolism has not been well elucidated. In this study, we generated LYCAT-defi cient mice and demonstrated that LYCAT determined the fatty acid composition of PI in vivo. LYCATdefi cient mice were outwardly healthy and fertile. In the mice, stearoyl-CoA acyltransferase activity toward the sn -1 position of PI was reduced, and the fatty acid composition of PI, but not those of other major phospholipids, was altered. Furthermore, expression of mouse LYCAT rescued the phenotype of C. elegans acl-8 acl-9 acl-10 triple mutants. Our data indicate that LYCAT is a determinant of PI molecular species and its function is conserved in C. elegans and mammals. Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O -acyltransferase; A-P axis, anterior-posterio axis; CL, cardiolipin; ER, endoplasmic reticulum; LPCAT, lysophosphatidylcholine acyltransferase; LPEAT, lysophosphatidylethanolamine acyltransferase; LPGAT, lysophosphatidylglycerol acyltransferase; LPIAT, lysophosphatidylinositol acyltransferase; LPSAT, lysophosphatidylserine acyltransferase; LYCAT, lysocardiolipin acyltransferase; MEF, mouse embryonic fi broblast; PC, phosphatidylcholi...

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“…In mammalian cells, two additional enzymes, lysocardiolipin acyltransferase 1 (AL-CAT1) and MLCL acyltransferase 1 (MLCL AT-1), can use acyl-CoAs to esterify MLCL ( 28 ). ALCAT1, however, is located on the ER, which would prevent its interaction with most CL ( 30 ), but MLCL AT-1 is present in mitochondria ( 11 ). Although overexpressing MLCL AT-1 in tafazzindefi cient lymphoblasts increases both linoleate incorporation into CL and total CL content ( 11 ), the importance of MLCL AT-1 for normal CL remodeling in heart cells remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function

Grevengoed

Martin

Katunga

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.orgIn order to metabolize long-chain fatty acids in pathways of ␤ -oxidation or the synthesis of complex lipids, they must fi rst be activated to acyl-CoAs by long-chain acyl-CoA synthetases (ACSLs). The fi ve mammalian ACSL isoforms each have a specifi c substrate preference, subcellular location, and tissue distribution ( 1 ). In the heart, the ACSL1 isoform predominates, such that with defi ciency, total ACSL specifi c activity and fatty acid oxidation decrease by more than 90% ( 2 ). Because ACSL activity is required for the incorporation of fatty acids into phospholipids, we asked whether the ACSL1 isoform is also required for the synthesis and remodeling of cardiac phospholipids, particularly cardiolipin (CL).The mitochondrial phospholipid CL contributes to many aspects of mitochondrial function, including energy production through oxidative phosphorylation ( 3, 4 ), mitochondrial fi ssion and fusion ( 5, 6 ), and cellular apoptosis ( 7 ). Tetralinoleoyl-CL is the predominant CL species in the mammalian heart ( 8 ), but the mechanism by which this species is formed is unclear. Because the enzymes of CL synthesis lack acyl-chain specifi city, nascent CL contains a mixture of acyl chain lengths and degrees of unsaturation ( 9 ). To obtain mature CL, most remodeling occurs within the mitochondria by sequentially removing each acyl chain to form monolyso-CL (MLCL) and then replacing the missing fatty acid with linoleate (18:2). Linoleate is added by transacylation from a donor phospholipid ( 10 ) or by direct esterifi cation of a linoleoyl-CoA ( 11, 12 ).The transacylase tafazzin is believed to be responsible for cardiolipin remodeling. Mutations in tafazzin cause Barth syndrome, an X-linked cardiomyopathy characterized by skeletal muscle weakness and heart failure in Abstract Long-chain acyl-CoA synthetase 1 (ACSL1) contributes more than 90% of total cardiac ACSL activity, but its role in phospholipid synthesis has not been determined. Mice with an inducible knockout of ACSL1 ( Acsl1 T ؊ / ؊ ) have impaired cardiac fatty acid oxidation and rely on glucose for ATP production. Because ACSL1 exhibited a strong substrate preference for linoleate, we investigated the composition of heart phospholipids.

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The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids

Cited by 50 publications

References 27 publications

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function

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