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Published on: May 20, 2018

纠正线粒体DNA中的METTL4-中介N6甲基酸过量减轻心力衰竭

Fuyang Zhang¹, Ling Zhang¹, Guangyu Hu¹

¹Departments of Cardiology (F.Z., L.Z., G.H., H.L., C.L., X.G., C.H., F.S., T.L., Z.C., Y.G., W.Y., Y.X., Z. Liu, Z. Lin, X.W., Z.W., S.W., L.T.), Xijing Hospital, Fourth Military Medical University, Xi'an, China.

|April 30, 2024

概括

心脏衰竭包括线粒体功能障碍. 科学家发现向改变线粒体DNA的酶METTL4可以恢复线粒体功能并治疗小鼠的心力衰竭.

科学领域:

心血管生物学
线粒体医学
表观遗传学

背景情况:

心肌线粒体功能障碍是心力衰竭 (HF) 发病的核心原因.
针对HF线粒体功能的治疗策略是有限的.
线粒体DNA (mtDNA) 的表观遗传修饰,如甲基化,在HF中的作用尚不清楚.

研究的目的:

研究心力衰竭期间线粒体DNA中N6-甲基亚丁 (6mA) 甲基化的作用.
确定甲基转移酶样蛋白4 (METTL4) 在调节mtDNA6mA中的功能及其对HF的贡献.

主要方法:

使用 angiotensin II/phenylephrine 输注或缺血/再输注损伤的实验性 HF 模型.
在衰竭的心肌细胞中通过质谱和ChIP测序特征化mtDNA6mA景观.
使用心肌细胞特异性Mettl4淘汰小鼠和AAV载体进行基因操纵.

主要成果:

在衰竭的成年心肌细胞中,METTL4和mtDNA6mA水平升高,与新生儿状况相关.
METTL4针对mtDNA促进体,破坏转录并导致线粒体功能障碍.
过度表达METTL4诱导HF表型,而METTL4删除或METTL4沉默改善了HF并恢复了线粒体功能.

结论:

由METTL4调节的心肌细胞mtDNA 6mA在HF病变和线粒体功能障碍中至关重要.
针对METTL4减少多余的mtDNA6mA代表了针对线粒体的HF干预的潜在治疗方法.

关键词:

DNA,线粒体心脏衰竭甲基化甲基转移酶线粒体疾病

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