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

Abstract

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.

Unremodeled and Remodeled Cardiolipin Are Functionally Indistinguishable in Yeast

“…Importantly, studies that previously reported abnormal mitochondrial morphology in ⌬crd1 and ⌬taz1 yeast never reported the penetrance of the observed defects (19,52). Furthermore, our results indicate that the genetic background contributes to mitochondrial morphology.…”

“…Miscellaneous-Isolation of mitochondria, preparation of yeast cell extracts, blue native-PAGE, mitochondrial respiration, phospholipid analysis, and immunoblotting were performed as described previously (12,18,52). Statistical comparisons were performed by one-way analysis of variance compared with wild type using SigmaPlot 11 software (Systat software, San Jose, CA).…”

“…Morphology-Altered mitochondrial morphology has been observed in ⌬crd1 and ⌬taz1 yeast (19,52). To determine what role, if any, CL remodeling plays in the establishment and/or maintenance of mitochondrial morphology, CL remodeling mutants were analyzed by EM (Fig.…”

Cardiolipin fingerprinting of leukocytes by MALDI-TOF/MS as a screening tool for Barth syndrome

“…CL is the signature lipid of mitochondria, where it is an important constituent of the inner membrane, essential for supercomplex formation, oxidative phosphorylation (i.e., mitochondrial energy metabolism), and protein import, and is capable of triggering mitophagy and mitochondria-mediated apoptosis (8)(9)(10)(11)(12)(13)(14)(15)(16). Because the remodeling of CL is deficient in BTHS, biochemical abnormalities in patients include a decreased level of mature CL (CLm), an increased level of monolysocardiolipin (MLCL), and altered CL acyl composition [i.e., the presence of immature CL (CLi) species].…”

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

“…Thus, potentially, many processes that result in impaired remodeling of cardiolipin through dysregulation of mitochondrial acyltransferases could result in decreased cardiolipin generation, mitochondrial structural anomalies and impairment in cellular bioenergetics. One such example is Barth syndrome, in which a mutation causes decreased tafazzin function, leading to a multitude of clinical effects, coupled with impaired cellular bioenergetics due to reduced biologically active cardiolipin (Claypool et al, 2008(Claypool et al, , 2006(Claypool et al, , 2011Whited et al, 2013).…”