Phospholipid abnormalities in children with Barth syndrome

Schlame, Michael; Kelley, Richard I.; Feigenbaum, Annette; Towbin, Jeffrey A.; Heerdt, Paul M.; Schieble, Thomas; Wanders, Ronald J. A.; DiMauro, Salvatore; Blanck, Thomas J. J.

doi:10.1016/j.jacc.2003.06.015

Cited by 188 publications

(190 citation statements)

References 25 publications

Supporting

Mentioning

181

Contrasting

Order By: Relevance

“…The model is also applicable to heart, where we described complementary changes in PC and CL of two BTHS patients. 10 In these two patients, cardiac 16:0-18:2-PC increased at the expense of 16:0-20:4-PC. This, together with the lack of 18:2 in CL, suggested that 18:2 was transferred from PC to CL and 20:4 was used to reacylate lyso-PC ( Figure 6).…”

Section: Discussionmentioning

confidence: 76%

“…10 Although the concentration of other phospholipids remained normal in BTHS, 10 it was not known whether or not the fatty acid composition of these phospholipids was affected as well. In the present study, we provided a comprehensive fatty acid analysis of PC, PE, and CL in lymphoblasts from BTHS patients and controls ( Table 1).…”

Section: Analysis Of Phospholipidsmentioning

confidence: 99%

“…CL is a dimeric phospholipid that is specific to mitochondria and has a unique fatty acid pattern. 8 The fatty acid pattern of CL is severely disturbed in heart, skeletal muscle, 9,10 platelets, [9][10][11] and neutrophils of BTHS patients. 12 The same phenomenon was observed in tafazzin-deficient yeast.…”

mentioning

confidence: 99%

“…15 In the absence of functional tafazzin, CL is unable to form certain molecular species (specific combinations of fatty acids in a single molecule), the concentration of CL is reduced, and there is accumulation of its degradation product, monolyso-CL. [9][10][11][12][13][14][15] BTHS is unique because it is the only cardiomyopathy whose origin is found in phospholipid metabolism. However, the molecular mechanism of the disease has not been understood.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Characterization of lymphoblast mitochondria from patients with Barth syndrome

Sutachán

Plesken

et al. 2005

Laboratory Investigation

Self Cite

132

128

View full text Add to dashboard Cite

Barth syndrome (BTHS) is a multisystem disorder of individuals who carry mutations in tafazzin, a putative phospholipid acyltransferase. We investigated the hypothesis that BTHS is caused by specific impairment of the mitochondrial lipid metabolism. The fatty acid composition of all major mitochondrial phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL), changed in lymphoblasts from BTHS patients. These changes were most extensive in CL and least extensive in PE. The complementary nature of the fatty acid alterations in CL and PC suggested that fatty acid transfer between these two lipids was inhibited in BTHS. Fluorescence staining and electron microscopy showed abnormal proliferation of mitochondria in BTHS lymphoblasts. The mitochondrial membrane potential, monitored with the fluorescence probe JC-1, was reduced in BTHS lymphoblasts. However, mitochondrial ATP formation of permeabilized lymphoblasts remained unaffected in BTHS. The data suggest that phospholipid abnormalities of BTHS mitochondria led to partial uncoupling of oxidative phosphorylation and that lymphoblasts compensated for this deficiency by expanding the mitochondrial compartment.

show abstract

Section: Discussionmentioning

confidence: 76%

Section: Analysis Of Phospholipidsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Characterization of lymphoblast mitochondria from patients with Barth syndrome

Sutachán

Plesken

et al. 2005

Laboratory Investigation

Self Cite

132

128

View full text Add to dashboard Cite

show abstract

“…BTHS is characterized by cardiac and skeletal myopathies and cyclic neutropenia (Barth et al, 1983(Barth et al, , 1999(Barth et al, , 2004; the disease presents in infants and if undiagnosed, is often fatal due to cardiac failure or sepsis. There are three hallmarks of the loss of Taz1p activity in the mitochondria of BTHS patients (Vreken et al, 2000;Valian-pour et al, 2002Valian-pour et al, , 2005Schlame et al, 2003;Schlame and Ren, 2006): 1) CL content is reduced; 2) CL contains more randomly distributed, saturated fatty acyl chains; and 3) there is an accumulation of monolysocardiolipin (MLCL). These three characteristics have been defined in the yeast Saccharomyces cerevisiae BTHS model (Vaz et al, 2003;Gu et al, 2004;Testet et al, 2005;Claypool et al, 2006); all but the accumulation of MLCL has been documented in the Drosophila melanogaster BTHS model (Xu et al, 2006a), and the mitochondrial phospholipids have not been characterized in the zebrafish BTHS model (Khuchua et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

Claypool¹,

Boontheung²,

McCaffery

et al. 2008

MBoC

100

View full text Add to dashboard Cite

Mutations in the mitochondrial cardiolipin (CL) transacylase, tafazzin (Taz1p), result in the X-linked cardioskeletal myopathy, Barth syndrome (BTHS). The mitochondria of BTHS patients exhibit variable respiratory defects and abnormal cristae ultrastructure. The biochemical basis for these observations is unknown. In the absence of its target phospholipid, CL, a very large Taz1p complex is missing, whereas several discrete smaller complexes are still observed. None of the identified Taz1p complexes represents Taz1p homodimers. Instead, yeast Taz1p physically assembles in several protein complexes of distinct size and composition. The ATP synthase and AAC2, both required for oxidative phosphorylation, are identified in separate stable Taz1p complexes. In the absence of CL, each interaction is still detected albeit in reduced abundance compared with when CL is present. Taz1p is not necessary for the normal expression of AAC2 or ATP synthase subunits or assembly of their respective complexes. In contrast, the largest Taz1p complex requires assembled ATP synthase and CL. Mitochondria in ⌬taz1 yeast, similar to ATP synthase oligomer mutants, exhibit altered cristae morphology even though ATP synthase oligomer formation is unaffected. Thus, the Taz1p interactome defined here provides novel insight into the variable respiratory defects and morphological abnormalities observed in mitochondria of BTHS patients.

show abstract

Response characteristics of the mitochondrial DNA genome in developmental health and disease

Knudsen

Green

2004

Birth Defects Research Pt C

View full text Add to dashboard Cite

This review focuses on mitochondrial biology in mammalian development; specifically, the dynamics of information transfer from nucleus to mitochondrion in the regulation of mitochondrial DNA genomic expression, and the reverse signaling of mitochondrion to nucleus as an adaptive response to the environment. Data from recent studies suggest that the capacity of embryonic cells to react to oxygenation involves a tradeoff between factors that influence prenatal growth/development and postnatal growth/function. For example, mitochondrial DNA replication and metabolic set points in nematodes may be determined by mitochondrial activity early in life. The mitochondrial drug PK11195, a ligand of the peripheral benzodiazepine receptor, has antiteratogenic and antidisease action in several developmental contexts in mice. Protein malnutrition during early life in rats can program mitochondrial DNA levels in adult tissues and, in humans, epidemiological data suggest an association between impaired fetal growth and insulin resistance. Taken together, these findings raise the provocative hypothesis that environmental programming of mitochondrial status during early life may be linked with diseases that manifest during adulthood. Genetic defects that affect mitochondrial function may involve the mitochondrial DNA genome directly (maternal inheritance) or indirectly (Mendelian inheritance) through nuclear-coded mitochondrial proteins. In a growing number of cases, the depletion of, or deletion in, mitochondrial DNA is seen to be secondary to mutation of key nuclear-coded mitochondrial proteins that affect mitochondrial DNA replication, expression, or stability. These defects of intergenomic regulation may disrupt the normal cross-talk or structural compartmentation of signals that ultimately regulate mitochondrial DNA integrity and copy number, leading to depletion of mitochondrial DNA.

show abstract

Phospholipid abnormalities in children with Barth syndrome

Abstract: Abnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations. These mutations lead to alterations in the fatty acid composition of several phospholipids, supporting the idea that TAZ encodes a human acyltransferase.

Cited by 188 publications

References 25 publications

Characterization of lymphoblast mitochondria from patients with Barth syndrome

Characterization of lymphoblast mitochondria from patients with Barth syndrome

The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome

Response characteristics of the mitochondrial DNA genome in developmental health and disease

Contact Info

Product

Resources

About