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

Quantitative and qualitative alterations of mitochondrial cardiolipin have been implicated in the pathogenesis of Barth syndrome, an X-linked cardioskeletal myopathy caused by a deficiency in tafazzin, an enzyme in the cardiolipin remodeling pathway. We have generated and previously reported a tafaz...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (7), p.2337-2341
Main Authors: Malhotra, Ashim, Edelman-Novemsky, Irit, Xu, Yang, Plesken, Heide, Ma, Jinping, Schlame, Michael, Ren, Mindong, Sabatini, David D.
Format: Article
Language:English
Subjects:
1-Acylglycerophosphocholine O-Acyltransferase - genetics
1-Acylglycerophosphocholine O-Acyltransferase - metabolism
Animals
Animals, Genetically Modified
Barth syndrome
Biological Sciences
Cardiolipins
Cardiolipins - metabolism
Chemical composition
Drosophila
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Gene Expression Regulation, Enzymologic
Humans
Individualization
Infertility, Male
Lymphocytes - metabolism
Lysophospholipids - metabolism
Male
Male infertility
Muscular Diseases - enzymology
Muscular Diseases - pathology
Phenotypes
Phospholipases A2, Calcium-Independent - metabolism
Renovations
Spermatids
Spermatogenesis
Syndrome
Transposons
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Summary:Quantitative and qualitative alterations of mitochondrial cardiolipin have been implicated in the pathogenesis of Barth syndrome, an X-linked cardioskeletal myopathy caused by a deficiency in tafazzin, an enzyme in the cardiolipin remodeling pathway. We have generated and previously reported a tafazzin-deficient Drosophila model of Barth syndrome that is characterized by low cardiolipin concentration, abnormal cardiolipin fatty acyl composition, abnormal mitochondria, and poor motor function. Here, we first show that tafazzin deficiency in Drosophila disrupts the final stage of spermatogenesis, spermatid individualization, and causes male sterility. This phenotype can be genetically suppressed by inactivation of the gene encoding a calcium-independent phospholipase A₂, iPLA2-VIA, which also prevents cardiolipin depletion/monolysocardiolipin accumulation, although in wild-type flies inactivation of the iPLA2-VIA does not affect the molecular composition of cardiolipin. Furthermore, we show that treatment of Barth syndrome patients' lymphoblasts in tissue culture with the iPLA₂ inhibitor, bromoenol lactone, partially restores their cardiolipin homeostasis. Taken together, these findings establish a causal role of cardiolipin deficiency in the pathogenesis of Barth syndrome and identify iPLA2-VIA as an important enzyme in cardiolipin deacylation, and as a potential target for therapeutic intervention.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0811224106