Myocardium-specific Isca1 knockout causes iron metabolism disorder and myocardial oncosis in rat
Myocardium-specific Isca1 knockout causes iron metabolism disorder and myocardial oncosis in rat
复制标题
心肌特异性 Isca1 敲除导致大鼠铁代谢紊乱和心肌坏死
DOI：
10.1016/j.lfs.2022.120485
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发表时间：
2022-03-16
期刊：
影响因子：
6.1
通讯作者：
Zhang, Lianfeng
中科院分区：
文献类型：
--
作者：
Ling, Yahao;Yang, Xinlan;Zhang, Lianfeng
目的：多发性线粒体功能障碍（multiple mitochondrial dysfunction，MMD）可导致线粒体结构和功能的复杂损伤，进而导致包括脑功能异常在内的多种代谢途径的严重损害。然而，MMD对心脏这一高度依赖于多巴胺的组织的影响尚不清楚。在本研究中，我们使用铁硫簇组装体1（Isca 1），它已被证明会导致MMD综合征5型（MMDS 5），以验证上述科学问题。主要方法：我们使用CRISPR-Cas9技术产生心肌特异性Isca 1敲除大鼠（Isca 1（flox/flox）/alpha-MHC-Cre）。超声心动图、磁共振成像（MRI）、组织病理学检查和分子标志物检测证实了该模型的表型特征。主要发现：本研究首次在体内证实了Ica 1缺乏对大鼠心脏发育的影响，即心肌细胞线粒体损伤，铁代谢紊乱，导致心肌细胞胀亡，最终导致心力衰竭和机体死亡。此外，正向和反向验证实验表明，前列腺六跨膜上皮抗原3（STEAP 3）是一种新的ISCA 1相互作用分子，在ISCA 1缺乏引起的铁代谢和能量生成障碍中起重要作用。这一结果为认识MMDS的发病机制，特别是心脏发育和心脏疾病的病理过程提供了理论依据，为寻找MMDS的临床治疗靶点提供了新的线索。
Aims: Multiple mitochondrial dysfunction (MMD) can lead to complex damage of mitochondrial structure and function, which then lead to the serious damage of various metabolic pathways including cerebral abnormalities. However, the effects of MMD on heart, a highly mitochondria-dependent tissue, are still unclear. In this study, we use iron-sulfur cluster assembly 1 (Isca1), which has been shown to cause MMD syndromes type 5 (MMDS5), to verify the above scientific question.Main methods: We generated myocardium-specific Isca1 knockout rat (Isca1(flox/flox)/alpha-MHC-Cre) using CRISPR-Cas9 technology. Echocardiography, magnetic resonance imaging (MRI), histopathological examinations and molecular markers detection demonstrated phenotypic characteristics of our model. Immunoprecipitation, immunofluorescence co-location, mitochondrial activity, ATP generation and iron ions detection were used to verify the molecular mechanism.Key findings: This study was the first to verify the effects of Isca1 deficiency on cardiac development in vivo, that is cardiomyocytes suffer from mitochondria damage and iron metabolism disorder, which leads to myocardial oncosis and eventually heart failure and body death in rat. Furthermore, forward and reverse validation experiments demonstrated that six-transmembrane epithelial antigen of prostate 3 (STEAP3), a new interacting molecule for ISCA1, plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency.Significance: This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching clinical therapeutic targets of MMDS.