Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Cells. 2020 Aug 11;9(8):1885. doi: 10.3390/cells9081885.
Mitochondrial dysfunction is involved in the pathogenesis of atherosclerosis, the primary risk factor for ischemic stroke. This study aims to explore the role of mitochondrial genomic variations in ischemic stroke, and to uncover the nuclear genes involved in this relationship. Eight hundred and thirty Taiwanese patients with a history of ischemic stroke and 966 normal controls were genotyped for their mitochondrial haplogroup (Mthapg). Cytoplasmic hybrid cells (cybrids) harboring different Mthapgs were used to observe functional differences under hypoxia-ischemia. RNA sequencing (RNASeq) was conducted to identify the particularly elevated mRNA. The patient study identified an association between Mthapg F1 and risk of ischemic stroke (OR 1.72:1.27-2.34, = 0.001). The cellular study further demonstrated an impeded induction of hypoxic inducible factor 1α in the Mthapg F1 cybrid after hypoxia-ischemia. Additionally, the study demonstrated that Mthapg F cybrids were associated with an altered mitochondrial function, including decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential. Mthapg F cybrids were also noted to be prone to inflammation, with increased expression of several inflammatory cytokines and elevated matrix metalloproteinase 9. The RNASeq identified significantly elevated expressions of angiopoietin-like 4 in Mthapg F1 cybrids after hypoxia-ischemia. Our study demonstrates an association between Mthapg F and susceptibility to ischemic stroke.
线粒体功能障碍与动脉粥样硬化的发病机制有关，而动脉粥样硬化是缺血性中风的主要危险因素。本研究旨在探讨线粒体基因组变异在缺血性中风中的作用，并揭示涉及这种关系的核基因。对 830 名有缺血性中风病史的台湾患者和 966 名正常对照进行了线粒体单倍型（Mthapg）的基因分型。使用携带不同 Mthapg 的细胞质杂种细胞（cybrids）观察缺氧缺血下的功能差异。进行 RNA 测序（RNASeq）以鉴定特别升高的 mRNA。患者研究发现 Mthapg F1 与缺血性中风风险之间存在关联（OR 1.72:1.27-2.34， = 0.001）。细胞研究进一步表明，在缺氧缺血后，Mthapg F1 cybrid 中缺氧诱导因子 1α 的诱导受到抑制。此外，该研究表明，Mthapg F cybrid 与改变的线粒体功能有关，包括氧消耗减少、线粒体 ROS 产生增加和线粒体膜电位降低。Mthapg F cybrid 也容易发生炎症，几种炎症细胞因子的表达增加，基质金属蛋白酶 9 升高。RNASeq 鉴定出缺氧缺血后 Mthapg F1 cybrid 中血管生成素样 4 的表达显著升高。本研究表明 Mthapg F 与缺血性中风易感性之间存在关联。
