Defective Remodeling of Cardiolipin and Phosphatidylglycerol in Barth Syndrome

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

“…In agreement with a role of Tafazzins in the reacylation of cardiolipin, accumulation of monolysocardiolipin has been observed in yeast taz1⌬ mitochondria (Vaz et al, 2003;Gu et al, 2004). Similarly, aberrant forms of cardiolipin are apparent in Barth syndrome patients (Vreken et al, 2000;Vaz et al, 2003;Xu et al, 2003;Gu et al, 2004). In higher eukaryotes, all enzymes that participate in the synthesis of cardiolipin downstream of phosphatidic acid have been localized to the inner mitochondrial membrane (for review see Schlame et al, 2000).…”

“…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).…”

“…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.…”

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

“…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).…”

Loss of Function ofKRE5Suppresses Temperature Sensitivity of Mutants Lacking Mitochondrial Anionic Lipids

“…CL plays a key role in mitochondrial bioenergetics (Jiang et al, 2000; Greenberg, 2000, 2002;Schlame et al, 2000;Pfeiffer et al, 2003) and is also involved in mitochondrial biogenesis (Kawasaki et al, 1999;Jiang et al, 2000). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (Vreken et al, 2000). The phenotype of Barth syndrome is dependent upon multiple factors that are not well understood (Barth et al, 1983(Barth et al, , 1996.…”