Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome
Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome
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DOI：
10.1073/pnas.0811224106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Ren, Mindong
中科院分区：
文献类型：
--
作者：
Malhotra, Ashim;Edelman-Novemsky, Irit;Ren, Mindong
线粒体心磷脂的定量和定性改变与Barth综合征的发病机制有关，Barth综合征是一种X连锁心脏骨骼肌病，由心磷脂重塑途径中的一种酶tafazzin缺乏引起。我们已经产生和以前报道了一个他法嗪缺陷的果蝇模型的巴特综合征，其特征是低心磷脂浓度，异常心磷脂脂肪酰基组成，异常线粒体，和运动功能差。在这里，我们首先表明，在果蝇tafazzin缺乏破坏精子发生的最后阶段，精子细胞个体化，并导致雄性不育。这种表型可以通过编码钙非依赖性磷脂酶A2（iPLA 2-VIA）的基因的失活而在遗传上受到抑制，这也防止了心磷脂消耗/单溶血心磷脂积累，尽管在野生型果蝇中iPLA 2-VIA的失活不影响心磷脂的分子组成。此外，我们表明，在组织培养中用iPLA 2抑制剂溴烯醇内酯处理巴斯综合征患者的淋巴母细胞，部分恢复了他们的心磷脂稳态。总而言之，这些发现确立了心磷脂缺乏在巴斯综合征发病机制中的因果作用，并确定iPLA 2-VIA是心磷脂脱酰化的重要酶，也是治疗干预的潜在靶点。
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.