Deletion of the Cardiolipin-specific Phospholipase Cld1 Rescues Growth and Life Span Defects in the Tafazzin Mutant

Ye, Cunqi; Lou, Wenjia; Li, Yiran; Chatzispyrou, Iliana A.; Hüttemann, Maik; Lee, Icksoo; Houtkooper, Riekelt H.; Vaz, Frédéric M.; Chen, Shuliang; Greenberg, Miriam L.

doi:10.1074/jbc.m113.529487

Cited by 57 publications

(87 citation statements)

References 93 publications

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“…Conversely, normalizing tetralinoleoyl-CL in Acsl1 T Ϫ / Ϫ hearts was not sufficient to improve mitochondrial respiratory function. Our data, together with the published yeast studies ( 25,26 ), suggest that the underlying diffi culty in Barth syndrome and tafazzin-defi cient mice is a defi ciency in CL content and/or the accumulation of MLCL.…”

Section: Acsl1 Activates Linoleate For Cardiolipin Remodelingmentioning

confidence: 84%

“…In Acsl1 T Ϫ / Ϫ hearts, normalizing the amount of linoleate present in CL did not improve respiratory dysfunction. Similarly, in S. cerevisiae , CL remodeling can be inhibited without impairing basal or ADP-stimulated mitochondrial O 2 consumption ( 25,26 ). Thus, in both yeast and in Acsl1…”

Section: Acsl1 Activates Linoleate For Cardiolipin Remodelingmentioning

confidence: 99%

“…The relevance of CL acyl-chain composition to normal oxidative phosphorylation is controversial ( 25,26 ). In order to determine whether the impaired respiratory function of mitochondria from Acsl1 T Ϫ / Ϫ hearts resulted from the presence of linoleate-defi cient mitochondrial CL, we fed control and Acsl1 T Ϫ / Ϫ mice a high saffl ower oil diet, in which 75% of the fatty acids are linoleate.…”

Section: Dietary Linoleate Enrichment Normalized Tetralinoleoyl-cl Comentioning

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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Section: Acsl1 Activates Linoleate For Cardiolipin Remodelingmentioning

confidence: 84%

Section: Acsl1 Activates Linoleate For Cardiolipin Remodelingmentioning

confidence: 99%

Section: Dietary Linoleate Enrichment Normalized Tetralinoleoyl-cl Comentioning

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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“…Two groups recently and independently showed that defined changes in the acyl chain composition of CL do not significantly alter either the mitochondrial morphology or mitochondrial bioenergetic functions in yeast (40,44). Both groups suggested alternative physiological roles for the CL remodeling process, for example a repair mechanism that removes and replaces acyl chains damaged by oxidative stress, thereby restoring the oxidative phosphorylation capacity of mitochondria (40,44).…”

Section: Discussionmentioning

confidence: 99%

“…Contribution of other enzymes to CL remodeling has been discussed such as Cld1 (43) and enzymes with lysophospholipid:acyl-CoA acyltransferase activity, MLCLAT1 (15) and ALCAT1 (16). In particular, Cld1, which is a CL-specific phospholipase and predominantly removes saturated acyl groups such as palmitoyl and stearoyl (18:0) groups (14), may play an important role in the initiation of CL remodeling in yeast mitochondria (40,44). The present observations that tafazzin could not efficiently remove the palmitoyl group from PC and CL support this notion.…”

Section: Discussionmentioning

confidence: 99%

Mechanism for Remodeling of the Acyl Chain Composition of Cardiolipin Catalyzed by Saccharomyces cerevisiae Tafazzin

Abe

Hasegawa

Oku

et al. 2016

Journal of Biological Chemistry

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Remodeling of the acyl chains of cardiolipin (CL) is responsible for final molecular composition of mature CL after de novo CL synthesis in mitochondria. Yeast Saccharomyces cerevisiae undergoes tafazzin-mediated CL remodeling, in which tafazzin serves as a transacylase from phospholipids to monolyso-CL (MLCL). In light of the diversity of the acyl compositions of mature CL between different organisms, the mechanism underlying tafazzin-mediated transacylation remains to be elucidated. We investigated the mechanism responsible for transacylation using purified S. cerevisiae tafazzin with liposomes composed of various sets of acyl donors and acceptors. The results revealed that tafazzin efficiently catalyzes transacylation in liposomal membranes with highly ordered lipid bilayer structure. Tafazzin elicited unique acyl chain specificity against phosphatidylcholine (PC) as follows: linoleoyl (18:2) > oleoyl (18:1) ‫؍‬ palmitoleoyl (16:1) > > palmitoyl (16:0). In these reactions, tafazzin selectively removed the sn-2 acyl chain of PC and transferred it into the sn-1 and sn-2 positions of MLCL isomers at equivalent rates. We demonstrated for the first time that MLCL and dilyso-CL have inherent abilities to function as an acyl donor to monolyso-PC and acyl acceptor from PC, respectively. Furthermore, a Barth syndrome-associated tafazzin mutant (H77Q) was shown to completely lack the catalytic activity in our assay. It is difficult to reconcile the present results with the so-called thermodynamic remodeling hypothesis, which premises that tafazzin reacylates MLCL by unsaturated acyl chains only in disordered non-bilayer lipid domain. The acyl specificity of tafazzin may be one of the factors that determine the acyl composition of mature CL in S. cerevisiae mitochondria.

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Remodelling of mitochondrial function by import of specific lipids at multiple membrane‐contact sites

Saukko‐Paavola,

Klemm

2024

FEBS Letters

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Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.

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Deletion of the Cardiolipin-specific Phospholipase Cld1 Rescues Growth and Life Span Defects in the Tafazzin Mutant

Cited by 57 publications

References 93 publications

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

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

Mechanism for Remodeling of the Acyl Chain Composition of Cardiolipin Catalyzed by Saccharomyces cerevisiae Tafazzin

Remodelling of mitochondrial function by import of specific lipids at multiple membrane‐contact sites

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