TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes
TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes
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DOI：
10.1038/s41467-019-12482-1
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发表时间：
2019-10-11
影响因子：
16.6
通讯作者：
Ruohola-Baker, Hannele
中科院分区：
文献类型：
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作者：
Miklas, Jason W.;Clark, Elisa;Ruohola-Baker, Hannele
线粒体三功能蛋白缺乏症是由于水合酶亚单位A(HADHA)突变引起的，导致婴儿猝死综合征，无法治愈。为了揭示疾病的病因，我们从HADHA缺陷的HiPSCs中培养出干细胞来源的心肌细胞，并通过一种上调表观遗传调节因子HOPX的工程microRNA成熟鸡尾酒来加速它们的成熟。在此，我们报道，用内源性脂肪酸混合物处理成熟的HADHA突变心肌细胞后，表现出疾病表型：钙动力学和复极动力学缺陷，导致前心律失常状态。单细胞RNA-seq揭示了一种基于代谢基因表达的心肌细胞发育中间产物。这种中间产物在对照细胞中产生成熟样心肌细胞，但突变细胞转变为病理状态，表现为脂肪酸β氧化减少、线粒体质子梯度降低、冠状结构破坏和心磷脂重塑缺陷。这项研究表明，HADHA(三功能蛋白α)是一种类似于单溶性心磷脂酰基转移酶的酶，是脂肪酸β氧化和心磷脂重塑所必需的，而这是人类心肌细胞功能线粒体所必需的。
Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.