METTL3 confers protection against mitochondrial dysfunction and cognitive impairment in an Alzheimer disease mouse model by upregulating Mfn2 via N6-methyladenosine modification

Author:

Chen Hao1ORCID,Xing Huaijie2,Zhong Changhui3,Lin Xuejuan1,Chen Ruipeng1,Luo Ning1,Chen Lijun1,Huang Yusheng1

Affiliation:

1. Department of Neurology, The First Affiliated Hospital of Hainan Medical University , Haikou, Hainan, P.R. China

2. Department of Neurology, The Second Affiliated Hospital of Hainan Medical University , Haikou, Hainan, P.R. China

3. Department of Intensive Care Unit, The First Affiliated Hospital of Hainan Medical University , Haikou, Hainan, P.R. China

Abstract

Abstract 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.

Funder

Natural Science Youth Project

Department of Science and Technology of Hainan Province in 2019

Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province in 2021

Publisher

Oxford University Press (OUP)

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