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

Department of Chemistry and Biochemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1569, USA.
Molecular biology of the cell (Impact Factor: 4.47). 10/2008; 19(12):5143-55. DOI: 10.1091/mbc.E08-09-0896
Source: PubMed


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 Delta 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.

8 Reads
  • Source
    • "It is thus not surprising that mitochondrial respiration and energy production are correlated with CL biosynthesis (Claypool et al. 2008a; Jiang et al. 2000; Gohil et al. 2004), and that CL deficiency resulting from abnormal CL remodeling disrupts energy dynamics. For example, tafazzin mutations lead to decreased CL content and defective bioenergetics in yeast (Ma et al. 2004; Claypool et al. 2008b) and mammals (Xu et al. 2005; McKenzie et al. 2006). As discussed above, this defect in yeast taz1Δ is due to the decrease in CL/MLCL, not to the decrease in unsaturated CL (Baile et al. 2014; Ye et al. 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiolipin (CL), the signature phospholipid of mitochondria, is involved in a plethora of cellular processes and is crucial for mitochondrial function and architecture. The de novo synthesis of CL in the mitochondria is followed by a unique remodeling process, in which CL undergoes cycles of deacylation and reacylation. Specific fatty acyl composition is acquired during this process, and remodeled CL contains predominantly unsaturated fatty acids. The importance of CL remodeling is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), caused by mutations in tafazzin, which reacylates monolysocardiolipin (MLCL) generated from the deacylation of CL. Just as CL-deficient yeast mutants have been instrumental in elucidating functions of this lipid, the recently characterized CL-phospholipase mutant cld1Δ and the tafazzin mutant taz1Δ are powerful tools to understand the functions of CL remodeling. In this review, we discuss recent advances in understanding the role of CL in mitochondria with specific focus on the enigmatic functions of CL remodeling.
    Journal of Bioenergetics 11/2014; DOI:10.1007/s10863-014-9591-7 · 3.21 Impact Factor
  • Source
    • "In addition to having a role in regulating protein import and activity, CL, as well as PE, is important for tubular mitochondrial morphology and membrane fusion [24–28]. Mitochondrial morphology depends on a balance between fusion and fission events. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial membrane phospholipids are essential for the mitochondrial architecture, the activity of respiratory proteins, and the transport of proteins into the mitochondria. The accumulation of phospholipids within mitochondria depends on a coordinate synthesis, degradation, and trafficking of phospholipids between the endoplasmic reticulum (ER) and mitochondria as well as intramitochondrial lipid trafficking. Several studies highlight the contribution of dietary fatty acids to the remodeling of phospholipids and mitochondrial membrane homeostasis. Understanding the role of phospholipids in the mitochondrial membrane and their metabolism will shed light on the molecular mechanisms involved in the regulation of mitochondrial function and in the mitochondrial-related diseases.
    International Journal of Cell Biology 01/2014; 2014(6):709828. DOI:10.1155/2014/709828
  • Source
    • "This trafficking of MLCL is expected to occur rapidly after CL deacylation as MLCL does not accumulate in yeast with a functional Taz1p (Baile et al., 2013; Gu et al., 2004). That both Cld1p and Taz1p assemble into higher-order complexes (Baile et al., 2013; Claypool et al., 2006, 2008a), and that their binding partners have been, at best, partially defined, raises the exciting possibility that the protein(s) mediating MLCL translocation physically interacts with Cld1p, Taz1p, or both enzymes, although this has yet to be tested. While proteins mediating phospholipid redistribution between membrane leaflets have been identified for the plasma membrane, Golgi, and endosomes (van Meer et al., 2008), considerably less is known about this process in the mitochondrion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The signature mitochondrial phospholipid cardiolipin plays an important role in mitochondrial function, and alterations in cardiolipin metabolism are associated with human disease. Topologically, cardiolipin biosynthesis and remodeling is complex. Precursor phospholipids must be transported from the ER, across the mitochondrial outer membrane to the matrix-facing leaflet of the inner membrane, where cardiolipin biosynthesis commences. Post-synthesis, cardiolipin undergoes acyl chain remodeling, requiring additional trafficking steps, before it achieves its final distribution within both mitochondrial membranes. This process is regulated at several points via multiple independent mechanisms. Here, we review the regulation and topology of cardiolipin biosynthesis and remodeling in the yeast Saccharomyces cerevisiae. Although cardiolipin metabolism is more complicated in mammals, yeast have been an invaluable model for dissecting the steps required for this process.
    Chemistry and Physics of Lipids 10/2013; 179. DOI:10.1016/j.chemphyslip.2013.10.008 · 2.42 Impact Factor
Show more


8 Reads
Available from