| Popis: |
Tetralinoleoyl cardiolipin (Cl₄) is a mitochondrial membrane phospholipid associated with numerous mitochondrial structural and functional proteins. Synthesis involves remodelling by tafazzin, an acyltransferase encoded by the TAZ gene. TAZ mutations result in Barth syndrome (BTHS), a rare disorder characterised by cardiomyopathy, skeletal myopathy, neutropenia, growth delay and 3-methylglutaconic aciduria. Clinical features are variable and diagnosis of the disorder is challenging. The pathogenesis of BTHS is unknown but may be due to deficiency of Cl₄ or to altered remodelling resulting in abnormal mitochondrial structure and function. The project's aims were to develop a method for analysis of Cl₄ and its precursor monolysocardiolipin (MLCL) for the diagnosis of BTHS, to use this method to determine the biochemical phenotype of BTHS patients, to identify new cases and to examine the effects of tafazzin deficiency on mitochondrial structure and function. A method for Cl₄ and MlCl analysis by lC-MS/MS was developed and used to analyse 34 BTHS and 76 control samples. lymphocytes and EBV-transformed lymphoblast cell lines were prepared from controls and BTHS patients. Mitochondria were examined by electron microscopy and apoptosis was assessed using flow cytometry. All BTHS patients had increased MlCl/Cl₄. Most had Cl₄ deficiency, but a subgroup was identified with normal Cl₄ and an ameliorated phenotype. BTHS lymphocytes had larger mitochondria and enhanced apoptosis compared with controls. EBV-transformation resulted in altered cardiolipin composition, increased number and size of mitochondria, abnormal cristae structure and increased apoptosis, with greater changes in BTHS Iymphoblasts. The data suggest that the pathogenesis of BTHS involves altered mitochondrial structure and enhanced apoptosis which are exacerbated following EBV infection. This is not due simply to Cl₄ deficiency, but may be due to alterations in the process of remodelling. Further work is required to elucidate how this results in a multisystem disorder with a highly variable phenotype. |
