The physical state of lipid substrates provides transacylation specificity for tafazzin

Schlame, Michael; Acehan, Devrim; Berno, Bob; Xu, Yang; Valvo, Salvatore; Ren, Mindong; Stokes, David L.; Epand, Richard M.

doi:10.1038/nchembio.1064

Cited by 106 publications

(146 citation statements)

References 41 publications

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“…Tafazzin has no acyl chain specificity (76). Thus, the acyl chain composition of remodeled CL may instead reflect the acyl chain composition of the surrounding lipids in the microenvironment containing tafazzin (77). Additionally, when compared with ⌬cld1, the acyl chain composition of CL in ⌬taz1 suggests that saturated acyl chains are the preferred substrate of Cld1p.…”

Section: Discussionmentioning

confidence: 99%

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

Baile¹,

Sathappa

Lu³

et al. 2014

Journal of Biological Chemistry

111

162

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Background:The phospholipid cardiolipin undergoes acyl chain remodeling after biosynthesis, which has been hypothesized to optimize mitochondrial function. Results: ⌬cld1 yeast, containing unremodeled cardiolipin, have no mitochondrial morphology or oxidative phosphorylation defects. Conclusion: Cardiolipin remodeling is not required for optimal mitochondrial bioenergetic function in yeast. Significance: Cardiolipin remodeling may be important for presently unknown mitochondrial processes and/or have unappreciated physiological functions.

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Section: Discussionmentioning

confidence: 99%

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

Baile¹,

Sathappa

Lu³

et al. 2014

Journal of Biological Chemistry

111

162

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“…Hearts with tafazzin loss-of-function mutations contain low levels of tetralinoleoyl-CL and have a high ratio of MLCL to CL. Because tafazzin does not have a substrate preference for linoleate, it has been proposed that the linoleate enrichment of CL must be due to either an alteration in the physical shape of CL or by the action of an additional enzyme ( 10 ).…”

Section: Mitochondrial Function Studiesmentioning

confidence: 99%

“…6A , B ). At this time, cells were incubated for an additional 24 h with a mixture of fatty acids to mimic the percentages in a physiological mixture of monounsaturated, saturated, and polyunsaturated fatty acids (30 µM oleate, 15 µM palmitate, and 5 µM linoleate plus the addition of 0.5 µCi of either [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]labeled oleate, palmitate, or linoleate). ACSL1 overexpression increased palmitate incorporation into total lipids by 43%, oleate incorporation by 49%, and linoleate incorporation by 75% ( Fig.…”

Section: Acsl1 Overexpression Increased Linoleate Incorporation Into mentioning

confidence: 99%

“…4 A-C ). To avoid high concentrations of fatty acid, which drives triacylglycerol synthesis, cells were incubated with trace amounts of individual [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C] fatty acids (palmitate, oleate, or linoleate) to measure their incorporation into phospholipids. As measured by ASMs in the media, the oxidation of these fatty acids was 80% lower in the Acsl1 knockdown cells than in controls ( Fig.…”

Section: Overexpressed Acsl1 Increased Linoleate Metabolismmentioning

confidence: 99%

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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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“…Many experimental and theoretical studies have examined membrane remodeling due to enzymatically driven changes in lipid composition (8). For instance, the disruption of the transacylase activity of the enzyme tafazzin leads to alterations in the mitochondrial lipid cardiolipin and the disease known as Barth's syndrome (9).…”

mentioning

confidence: 99%

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

Brea

Rudd

Devaraj

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/ acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.L iving organisms carry out the de novo synthesis of phospholipid membranes, in part, by using membrane-bound acyltransferases and reactive thioester precursors ( Fig. 1A) (1). Subsequently, de novo synthesized phospholipid membranes can be remodeled by acyltransferases and transacylases in the presence of different lysolipid, phospholipid, and fatty acid precursors ( Fig. 1A) (2). Such natural mechanisms allow cells to fine-tune properties of biological membranes by changing the composition and organization of their constituent lipids and proteins (3). Membrane remodeling is an essential component of numerous cellular functions including the formation of organelles (4), division (5), trafficking (6), and signaling (7). Many experimental and theoretical studies have examined membrane remodeling due to enzymatically driven changes in lipid composition (8). For instance, the disruption of the transacylase activity of the enzyme tafazzin leads to alterations in the mitochondrial lipid cardiolipin and the disease known as Barth's syndrome (9).Model membranes composed of well-defined synthetic lipids are useful tools for studying questions related to membrane biology (10, 11). The importance of lipid remodeling in biology underscores the need for straightforward methods to remodel lipid composition in artificial model membranes. Unfortunately, nonenzymatic methods to exchange lysolipid fragments in synthetic vesicles have previously not been feasible. This is likely due to the high kinetic stability of phospholipid membranes, which do not readily exchange diacylphospholipid species between membranes (12). Because the composition of phospholipids c...

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The physical state of lipid substrates provides transacylation specificity for tafazzin

Cited by 106 publications

References 41 publications

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

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

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

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