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Role of Calcium-Independent Phospholipase A2 in the Pathogenesis of Barth Syndrome

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Role of Calcium-Independent Phospholipase A2 in the Pathogenesis of Barth Syndrome Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome Ashim Malhotraa, Irit Edelman-Novemskyb, Yang Xua, Heide Pleskenb, Jinping Mab, Michael Schlamea,b, and Mindong Renb,1 Departments of bCell Biology and aAnesthesiology, New York University Langone Medical Center, New York, NY 10016 Edited by David D. Sabatini, New York University School of Medicine, New York, NY, and approved December 23, 2008 (received for review November 6, 2008) Quantitative and qualitative alterations of mitochondrial cardio- is required for maintaining not only the normal CL fatty acyl lipin have been implicated in the pathogenesis of Barth syndrome, composition, but also normal CL levels. an X-linked cardioskeletal myopathy caused by a deficiency in Although it has been established that tafazzin deficiency tafazzin, an enzyme in the cardiolipin remodeling pathway. We causes both Barth syndrome and a derangement of CL metab- have generated and previously reported a tafazzin-deficient Dro- olism, evidence that it is, in fact, the CL deficiency that con- sophila model of Barth syndrome that is characterized by low tributes to Barth syndrome has been circumstantial (15). To cardiolipin concentration, abnormal cardiolipin fatty acyl compo- elucidate the pathogenic mechanism of Barth syndrome and to sition, abnormal mitochondria, and poor motor function. Here, we identify potential targets for therapeutic intervention, we have first show that tafazzin deficiency in Drosophila disrupts the final created a Drosophila model of Barth syndrome (7) by knocking stage of spermatogenesis, spermatid individualization, and causes out the tafazzin gene and have asked whether the resulting male sterility. This phenotype can be genetically suppressed by phenotypic changes can be suppressed by partially restoring CL inactivation of the gene encoding a calcium-independent phos- homeostasis without correcting the tafazzin defect. Because reacylation of monolyso-CL is reduced due to tafazzin deficiency pholipase A2, iPLA2-VIA, which also prevents cardiolipin depletion/ monolysocardiolipin accumulation, although in wild-type flies in- in Barth syndrome and a new steady state of low CL and high activation of the iPLA2-VIA does not affect the molecular monolyso-CL is reached, we reasoned that an inhibition of composition of cardiolipin. Furthermore, we show that treatment mitochondrial phospholipase A2 activity could reverse these of Barth syndrome patients’ lymphoblasts in tissue culture with the phenotypic effects, even though CL molecules would still have an abnormal fatty acyl chain composition. Here, we identify a iPLA inhibitor, bromoenol lactone, partially restores their cardio- 2 calcium-independent phospholipase A , iPLA2-VIA, as an im- lipin homeostasis. Taken together, these findings establish a 2 portant enzyme in CL deacylation and monolyso-CL accumu- causal role of cardiolipin deficiency in the pathogenesis of Barth lation in Barth syndrome, and show that genetic inactivation of syndrome and identify iPLA2-VIA as an important enzyme in iPLA2-VIA suppresses the phenotype caused by tafazzin defi- cardiolipin deacylation, and as a potential target for therapeutic ciency in Drosophila. intervention. MEDICAL SCIENCES Results ͉ ͉ ͉ cardiolipin Drosophila iPLA2 tafazzin Tafazzin Deficiency Causes Male Sterility in Drosophila. Like Barth syndrome patients, the Drosophila model flies that we generated arth syndrome (MIM 302060) is caused by mutations in the (7) have CL deficiency, abnormal mitochondria, and poor motor BX-linked tafazzin gene (TAZ) (1), which encodes a mito- function. We now report that, in addition, Drosophila males chondrial phospholipid-lysophospholipid transacylase required homozygous for TAZ deletion mutations are also sterile (Fig. for cardiolipin (CL) homeostasis (2). In eukaryotes, CL is 1A). We ruled out the possibility that the male sterility might be present exclusively in the membranes of mitochondria, where it caused by other mutations present on the same chromosome interacts with a number of mitochondrial proteins and is essen- with the TAZ mutation, because the males compoundly het- tial for optimal mitochondrial functions (3–6). Defective tafazzin erozygous for those deletions were also sterile. These observa- results in CL deficiency (7–10) and, not surprisingly, patients tions strongly suggested that the inactivation of the defective with Barth syndrome present symptoms, such as cardioskeletal tafazzin gene is the cause of male sterility. We proved that this myopathy and exercise intolerance, which are commonly asso- is indeed the case, because transgenic expression of full-length ciated with mitochondrial diseases (11). Drosophila tafazzin, driven by GAL4 under the ubiquitously In mitochondria, CL is synthesized de novo through conden- active daughterless (da) promoter, rescued both the male sterile sation of phosphatidylglycerol (PG) with cytidine diphosphate- phenotype (Fig. 1A) and the CL deficiency in TAZ deletion diacylglycerol (CDP-DAG) catalyzed by cardiolipin synthase mutants (Fig. 1B). The easily identifiable male sterility pheno- (CLS) (3). Newly synthesized CL molecules are remodeled by type allowed us to examine the effect of second gene mutations transacylation catalyzed by tafazzin to yield the characteristic in the Barth model flies. steady-state acyl composition of the specific cells and tissues (6). Spermatid Individualization Is Disrupted in Tafazzin-Deficient Dro- In cells from Barth syndrome patients, because of defective sophila Males. The most common cause of male sterility in tafazzin, CL molecules fail to reach the normal fatty acyl Drosophila is defective spermatogenesis (16). Electron micro- composition (9, 10, 12). In addition, the level of total CL decreases despite normal de novo synthesis of CL molecules, and CL degradation intermediates, monolyso-CLs, accumulate (13, Author contributions: M.S. and M.R. designed research; A.M., I.E.-N., Y.X., H.P., J.M., M.S., 14). These features of tafazzin-deficient cells suggest that normal and M.R. performed research; A.M., I.E.-N., Y.X., M.S., and M.R. analyzed data; and M.R. steady-state levels of CL are maintained by at least 3 enzymatic wrote the paper. reactions: (i) de novo synthesis catalyzed by cardiolipin synthase, The authors declare no conflict of interest. (ii) deacylation of CL to monolyso-CL catalyzed by a mitochon- This article is a PNAS Direct Submission. drial phospholipase A, and (iii) reacylation of monolyso-CL 1To whom correspondence should be addressed. E-mail: [email protected]. catalyzed by tafazzin. Thus, the transacylase activity of tafazzin © 2009 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0811224106 PNAS ͉ February 17, 2009 ͉ vol. 106 ͉ no. 7 ͉ 2337–2341 Downloaded by guest on September 26, 2021 Fig. 1. Transgenic expression of full-length tafazzin restores male fertility and the normal cardiolipin profile of TAZ-deletion mutant flies. (A) Male Fig. 2. Cross-section electron micrographs through preindividualized (A and fertility of the tafazzin mutant flies without (TAZϪ/Ϫ) or with (TAZϪ/Ϫ; B) and mature (C and D) portions of spermatogenic cysts from wild-type (A and TG-TAZ) the transgenic expression of tafazzin gene driven by GAL4 relative to C) and TAZ deletion mutant (B and D) testes. Preindividualized spermatogenic the fertility of wild-type flies (WT). Data from 3 independent experiments. (B) cysts are similar in TAZϪ/Ϫ (B) and wild-type (A) testes. These cysts are Fluorescence HPLC cardiolipin profiles from WT, TAZϪ/Ϫ, and (TAZϪ/Ϫ; TG- identifiable by their light-staining major mitochondrial derivatives (big ar- TAZ) flies. The fluorescence yield (ordinate) is plotted against retention time row), in which an electron-dense material accumulates, enlarged minor mi- (abscissa). In normal Drosophila, because of cardiolipin remodeling, peak 2, tochondrial derivatives (small arrow), and the presence of extensive cytoplasm which contains a mixture of cardiolipin molecules with palmitoleoyl (16:1) and between the axonemes (arrow head). After individualization, wild-type cysts linoleoyl (18:2) residues (see ref. 25), is the dominant component. This peak is contain highly ordered arrays of elongated spermatids that have undergone markedly reduced in the TAZϪ/Ϫ mutant and is restored to nearly normal a significant reduction in the amount of cytoplasm that can be seen between levels in the transgenic flies. the sperm tails (C). TAZ mutant cysts fail to undergo proper individualization and in them spermatid arrangements are grossly disorganized (D). (Scale bar, 1 ␮m.) scopic examination of the testes of tafazzin-deficient males (Fig. 2) revealed no abnormalities in spermatogenesis until the stage of spermatid individualization, the terminal differentiation pro- iPLA2s, platelet-activating factor acetylhydrolases (PAF-AH), cess that transforms elongated syncytial spermatids within sper- and lysosomal PLA2s (19). The most likely candidate for car- matogenic cysts into individual spermatozoa (17, 18). In the diolipin deacylation in vivo would be iPLA2-VIA, a calcium- testes of tafazzin-deficient males, elongated syncytial spermatids independent phospholipase A2 that has been localized to mito- within the cysts contained normal axonemes and mitochondrial chondria (20, 21) and has a well-known function in phospholipid derivatives (Fig. 2B), but no highly ordered bundles of individual remodeling (19). The Drosophila ortholog of the mammalian spermatids, like those in wild-type testes (Fig. 2C), were
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