Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom being cardiomyopathy. In the tafazzin-deficient heart, cardiolipin (CL) acyl chains become abnormally heterogeneous unlike those in the normal heart with a single dominant linoleoyl species, tetralinoleoyl CL. In addition, the amount of CL decreases and monolysocardiolipin (MLCL) accumulates. Here we determine using high-resolution ³¹P nuclear magnetic resonance with cryoprobe technology the fundamental phospholipid composition, including the major but oxidation-labile plasmalogens, in the tafazzin-knockdown (TAZ-KD) mouse heart as a model of Barth syndrome. In addition to confirming a lower level of CL (6.4 ± 0.1 → 2.0 ± 0.4 mol % of the total phospholipid) and accumulation of MLCL (not detected → 3.3 ± 0.5 mol %) in the TAZ-KD, we found a substantial reduction in the level of plasmenylcholine (30.8 ± 2.8 → 18.1 ± 3.1 mol %), the most abundant phospholipid in the control wild type. A quantitative Western blot revealed that while the level of peroxisomes, where early steps of plasmalogen synthesis take place, was normal in the TAZ-KD model, expression of Far1 as a rate-determining enzyme in plasmalogen synthesis was dramatically upregulated by 8.3 (±1.6)-fold to accelerate the synthesis in response to the reduced level of plasmalogen. We confirmed lyso-plasmenylcholine or plasmenylcholine is a substrate of purified tafazzin for transacylation with CL or MLCL, respectively. Our results suggest that plasmenylcholine, abundant in linoleoyl species, is important in remodeling CL in the heart. Tafazzin deficiency thus has a major impact on the cardiac plasmenylcholine level and thereby its functions.

中文翻译：

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与 Tafazzin 缺乏症相关的心脏缩醛磷脂显着减少


Tafazzin 是一种线粒体酶，在重塑过程中催化磷脂和溶血磷脂之间的转酰基化。tafazzin 突变会导致 Barth 综合征，这是一种可能危及生命的疾病，主要症状是心肌病。在 tafazzin 缺陷的心脏中，心磷脂 （CL） 酰基链变得异常异质，这与正常心脏中具有单一主要亚油酰种类四亚油酰 CL 的酰基链不同。此外，CL 量减少，单溶酶心磷脂 （MLCL） 积累。在这里，我们使用高分辨率 ³¹P 核磁共振和低温探针技术确定 tafazzin-knockdown （TAZ-KD） 小鼠心脏中的基本磷脂组成，包括主要但不氧化的缩醛磷脂，作为 Barth 综合征的模型。除了确认 TAZ-KD 中 CL 水平较低 （总磷脂的 6.4 ± 0.1 → 2.0 ± 0.4 mol %）和 MLCL 的积累（未→检测到 3.3 ± 0.5 mol %），我们还发现血浆胆碱 （30.8 ± 2.8 → 18.1 ± 3.1 mol %）的水平显著降低，这是对照野生型中最丰富的磷脂。定量蛋白质印迹显示，虽然在 TAZ-KD 模型中，缩醛磷脂合成发生早期步骤的过氧化物酶体水平是正常的，但 Far1 作为缩醛磷脂合成中速率决定酶的表达显着上调 8.3 （±1.6） 倍，以加速合成以响应缩醛磷脂水平的降低。我们证实溶血儿胞膜酰胆碱或胞浆胆碱是纯化的 tafazzin 的底物，分别用于与 CL 或 MLCL 进行转酰基化。我们的结果表明，血浆胆碱在亚油酰物种中含量丰富，对重塑心脏 CL 很重要。 因此，Tafazzin 缺乏症对心脏血浆胆碱水平及其功能有重大影响。