Aberrant cardiolipin metabolism in the yeast <i>taz1</i> mutant: a model for Barth syndrome

Gu, Zhiming; Valianpour, Fredoen; Chen, Shuliang; Vaz, Frédéric M.; Hakkaart, G.A.J.; Wanders, Ronald J. A.; Greenberg, Miriam L.

doi:10.1046/j.1365-2958.2003.03802.x

Cited by 190 publications

(207 citation statements)

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“…Tafazzins mediate the late steps in the cardiolipin biosynthesis pathway, namely the acyl modifications that lead to its characteristic acyl pattern (Vreken et al, 2000;Vaz et al, 2003;Xu et al, 2003;Gu et al, 2004). Although human mitochondria predominantly contain cardiolipin with unsaturated C 18 fatty acids, cardiolipin of yeast contains equal amounts of oleoyl (18:1) and palmitoleoyl (C16:1; Jakovcic et al, 1971).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported a growth defect for taz1⌬ cells on nonfermentable media at elevated temperature (Vaz et al, 2003;Gu et al, 2004). While analyzing the functionality of the Taz1 HA at different temperatures, we compared the growth of cells expressing Taz1 HA to wild type and the taz1⌬ mutant.…”

Section: Effect Of Taz1 Deletion On Inner Membrane Protein Complexesmentioning

confidence: 99%

“…Sequence analyses demonstrate that the Taz protein is highly conserved from yeast to man and that it displays sequence similarity to acyltransferases that participate in the metabolism of phospholipids (Neuwald, 1997). Phospholipid analyses of fibroblasts from patients and yeast taz1⌬ mutant cells show reduced cardiolipin levels and an altered acyl chain composition (Vreken et al, 2000;Vaz et al, 2003;Xu et al, 2003;Gu et al, 2004).Cardiolipin is formed by two glycerol-linked phosphatidyl moieties. The four acyl side chains are usually monoand di-unsaturated fatty acids in higher eukaryotes.…”

mentioning

confidence: 99%

“…The reduced stability of these protein complex oligomers reflects the complete loss of cardiolipin from the mitochondrial membranes (Pfeiffer et al, 2003). In contrast to crd1⌬, yeast taz1⌬ mutant mitochondria still possess cardiolipin, although in reduced amounts and with altered structure (Vaz et al, 2003;Gu et al, 2004). It is so far unknown if and how the reduced levels of cardiolipin and the altered cardiolipin acyl side chain composition found in yeast taz1⌬ mutant cells or in Barth patients affect the respiratory chain supercomplexes.…”

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Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

190

150

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The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1⌬ mitochondria and show that these are destabilized in taz1⌬ mitochondria. This leads to a selective release of a complex IV monomer from the III 2 IV 2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1⌬ mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria. INTRODUCTIONBarth Syndrome is an X-linked recessive disorder that is characterized by cardioskeletal myopathy, neutropenia, increased urine levels of 3-methylglutaconic acid, abnormal mitochondria, and respiratory chain dysfunction (Barth et al., 1983(Barth et al., , 1996Kelley et al., 1991;D'Adamo et al., 1997). The disease is often fatal in infancy and early childhood because of cardiac failure and bacterial infections (Barth et al., 2004). Bione et al. (1996) identified the gene responsible, termed Tafazzin (TAZ), and localized it to region q28 on the X chromosome. Sequence analyses demonstrate that the Taz protein is highly conserved from yeast to man and that it displays sequence similarity to acyltransferases that participate in the metabolism of phospholipids (Neuwald, 1997). Phospholipid analyses of fibroblasts from patients and yeast taz1⌬ mutant cells show reduced cardiolipin levels and an altered acyl chain composition (Vreken et al., 2000;Vaz et al., 2003;Xu et al., 2003;Gu et al., 2004).Cardiolipin is formed by two glycerol-linked phosphatidyl moieties. The four acyl side chains are usually monoand di-unsaturated fatty acids in higher eukaryotes. Remodeling of cardiolipin through a cycle of deacylation and successive reacylation leads to the final and specific acyl composition. In heart and skeletal muscle mitochondria the tetralinoleoyl species predominates Xu et al., 2003;Hatch, 2004). Cardiolipin is primarily found in the mitochondrial membranes of eukaryotes (Hoch, 1992) and the bacterial cytoplasmic membrane. Although the molecular function of cardiolipin is still unclear, several studies have suggested that it is required for the proper function of some proteins and protein complexe...

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Taz1 Deletion On Inner Membrane Protein Complexesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

190

150

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“…Lipids were extracted from the lyophilized cell pellets using the previously reported method [33]; 25 μL of heptadecanoic acid ethyl ester was used as the internal standard. FAEEs in the total lipid extracts were purified by preparative TLC [9] using TLC Silica gel 60 F254plates (Merck, Darmstadt, Germany) and the solvent system of heptane, 2-propanol and acetic acid in the ratio 95:5:1 (v/v/v).…”

Section: Methodsmentioning

confidence: 99%

Functional expression and characterization of five wax ester synthases in Saccharomyces cerevisiae and their utility for biodiesel production

Shi

Valle-Rodríguez

Khoomrung

et al. 2012

Biotechnol Biofuels

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Background Wax ester synthases (WSs) can synthesize wax esters from alcohols and fatty acyl coenzyme A thioesters. The knowledge of the preferred substrates for each WS allows the use of yeast cells for the production of wax esters that are high-value materials and can be used in a variety of industrial applications. The products of WSs include fatty acid ethyl esters, which can be directly used as biodiesel. Results Here, heterologous WSs derived from five different organisms were successfully expressed and evaluated for their substrate preference in Saccharomyces cerevisiae . We investigated the potential of the different WSs for biodiesel (that is, fatty acid ethyl esters) production in S. cerevisiae . All investigated WSs, from Acinetobacter baylyi ADP1, Marinobacter hydrocarbonoclasticus DSM 8798, Rhodococcus opacus PD630, Mus musculus C57BL/6 and Psychrobacter arcticus 273-4, have different substrate specificities, but they can all lead to the formation of biodiesel. The best biodiesel producing strain was found to be the one expressing WS from M. hydrocarbonoclasticus DSM 8798 that resulted in a biodiesel titer of 6.3 mg/L. To further enhance biodiesel production, acetyl coenzyme A carboxylase was up-regulated, which resulted in a 30% increase in biodiesel production. Conclusions Five WSs from different species were functionally expressed and their substrate preference characterized in S. cerevisiae , thus constructing cell factories for the production of specific kinds of wax ester. WS from M. hydrocarbonoclasticus showed the highest preference for ethanol compared to the other WSs, and could permit the engineered S. cerevisiae to produce biodiesel.

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Molecular Genetics of Barth Syndrome

Takeda

2013

Encyclopedia of Life Sciences

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Barth syndrome (OMIM # 302060 ) (BTHS) is an X‐linked disorder of lipid metabolism characterised by cardiomyopathy, skeletal myopathy, neutropaenia, growth delays and 3‐methylglutaconic aciduria. The causative mutations for BTHS are in the TAZ gene, which encode a putative acyltransferase named tafazzin, involved in the remodelling of cardiolipin (CL) in the inner mitochondrial membranes. To date, more than 120 different disease‐causing TAZ gene mutations have been reported. Mutations in the TAZ gene cause accumulation of monolysoCL and reduced levels of tetralinoeoyl CL, which result in mitochondrial structural and functional abnormalities. The functional role of CL has been investigated using model systems for BTHS such as yeast, zebrafish and flies. Recently, an inducible tafazzin knockdown mouse demonstrated abnormal fetal heart development with altered mitochondrial ultrastructure. Current understanding of the molecular genetics of BTHS including CL metabolism, mitochondrial disorders and clinical presentations are reviewed. Key Concepts: Barth syndrome is an X‐linked disorder of lipid metabolism characterised by cardiomyopathy, skeletal myopathy, neutropaenia, growth delays and 3‐methylglutaconic aciduria. Barth syndrome is recognised as cardiolipin remodelling disorder due to the TAZ mutation. TAZ gene encodes tafazzin protein, which has a central role in the reacylation of MLCL to L4‐CL in the mitochondria. Cardiolipin plays a crucial role for both mitochondrial membrane structure and function. The role of tafazzin and cardiolipin in the mitochondria remains to be elucidated. Several model systems for Barth syndrome have been developed to elucidate the disease pathophysiology. Mouse model of Barth syndrome provide new insight into the role of tafazzin.

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Aberrant cardiolipin metabolism in the yeast taz1 mutant: a model for Barth syndrome

Cited by 190 publications

References 35 publications

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Functional expression and characterization of five wax ester synthases in Saccharomyces cerevisiae and their utility for biodiesel production

Molecular Genetics of Barth Syndrome

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