Mitofusin 2 (MFN2) has been found to be downregulated in patients with Alzheimer disease (AD) but little is known about its roles in the pathogenesis of AD. We explored the mechanism of N6-methyladenosine (m6A) methylation of Mfn2 in hippocampal mitochondrial dysfunction in an AD mouse model. APP/PS1 transgenic mice underwent stereotaxic injection of adeno-associated viruses and their behaviors were assessed. METTL3 and MFN2 expressions were measured by qRT-PCR and Western blot, accompanied by assessment of mitochondrial morphology, ATP, mitochondrial membrane potential, and amyloid-β content. Binding between METTL3 and MFN2, the total amount of m6A, and the m6A modification of Mfn2 were also determined. METTL3 and MFN2 were downregulated in hippocampal tissues of the AD model mice; METTL3 enhanced MFN2 expression via m6A modification. Overexpression of METTL3 or MFN2 ameliorated mitochondrial dysfunction indicated by fewer damaged mitochondria, increased ATP and JC-1 levels, and reduced Aβ content; improved cognitive impairment in the mice was indicated by the novel object discrimination index and Morris water maze tests. Effects of METTL3 overexpression were abrogated by further knockdown of MFN2. Thus, METTL3 ameliorated mitochondrial dysfunction and cognitive impairment in the AD model mice by increasing MFN2 expression via m6A modification.

中文翻译：

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METTL3 通过 N6-甲基腺苷修饰上调 Mfn2，为阿尔茨海默病小鼠模型提供针对线粒体功能障碍和认知障碍的保护

研究发现，线粒体融合蛋白 2 (MFN2) 在阿尔茨海默病 (AD) 患者中表达下调，但人们对其在 AD 发病机制中的作用知之甚少。我们探讨了 AD 小鼠模型中 Mfn2 的 N6-甲基腺苷 (m6A) 甲基化在海马线粒体功能障碍中的机制。APP/PS1 转基因小鼠接受腺相关病毒立体定位注射，并评估其行为。通过 qRT-PCR 和 Western blot 测量 METTL3 和 MFN2 的表达，同时评估线粒体形态、ATP、线粒体​​膜电位和淀粉样蛋白-β 含量。还测定了 METTL3 和 MFN2 之间的结合、m6A 的总量以及 Mfn2 的 m6A 修饰。AD模型小鼠海马组织中METTL3和MFN2表达下调；METTL3 通过 m6A 修饰增强 MFN2 表达。METTL3 或 MFN2 的过表达可改善线粒体功能障碍，表现为线粒体损伤减少、ATP 和 JC-1 水平增加以及 Aβ 含量降低；新物体辨别指数和莫里斯水迷宫测试表明小鼠认知障碍得到改善。METTL3 过表达的影响可通过进一步敲低 MFN2 消除。因此，METTL3 通过 m6A 修饰增加 MFN2 表达，从而改善 AD 模型小鼠的线粒体功能障碍和认知障碍。