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Prevalent N6-methyldeoxyadenosine methylation in mammalian mitochondrial DNA

ABSTRACT: N6-methyldeoxyadenosine (6mA or m6dA), a well-known prokaryotic DNA modification has recently been shown to exist and play regulatory roles in eukaryotic genomic DNA. However, biological functions of 6mA in mammals remain to be explored largely due to its low abundance in most mammalian genomes. Here, we report a significant enrichment of 6mA in mammalian mitochondrial DNA (mtDNA), and identify METTL4 as a methyltransferase that installs 6mA. The level of 6mA in mtDNA is elevated up to over 0.02% of the total deoxyadenosines under hypoxia, representing ~7,00-fold enrichment over 6mA in the genomic DNA (gDNA) under normal growth conditions. The presence of 6mA negatively regulates mitochondrial transcription and balances mitochondrial function for cellular adaption to hypoxic stress. While DNA 5-methylcytosine (5mC) is a well-established, prevalent epigenetic mark in mammalian genomic DNA, our study reveals for the first time DNA 6mA methylation as a regulatory mark in mammalian mtDNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102670 | GEO | 2020/03/24

REPOSITORIES: GEO

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Project description:BACKGROUND: Mitochondrial dysfunction is a key factor in the development of atherogenesis. Methyltransferase-like protein 4 (METTL4) mediates N6-deoxyadenosine (6mA) methylation of mammalian mitochondrial DNA (mtDNA). However, the role of METTL4-mediated mitoepigenetic regulation in atherosclerosis is still unknown. This study aims to investigate the potential involvement of METTL4 in atherosclerosis, explore the underlying mechanism, and develop targeted strategies for treating atherosclerosis. METHODS: Expression levels of mtDNA 6mA and METTL4 were determined in atherosclerotic lesions. We explored the mechanism of METTL4 involvement in atherosclerosis using Mettl4Mac-KO-Apoe-/- and Mettl4MUT-Apoe-/- mice and cell models, as well as bone marrow transplantation. Natural compound libraries were screened to identify potent METTL4 antagonists. In addition, bioinspired proteolysis-targeting (PROTAC) technology targeting macrophages within plaques was used to increase the efficacy of the METTL4 antagonist. RESULTS: The expression levels of mtDNA 6mA and METTL4 were significantly increased in plaque macrophages. Mettl4Mac-KO-Apoe-/- mice displayed suppressed mtDNA 6mA levels and atherosclerotic progression, which were reversed by METTL4 restoration via bone marrow transplantation (n = 6). Mechanistically, elevated METTL4 expression reduces MT-ATP6 expression by suppressing its transcription, thereby impairing the activity of mitochondrial respiration chain complex V. This disruption leads to the accumulation of excess protons in the mitochondrial intermembrane space, causing mitochondrial dysfunction. Consequently, mtDNA is released into the cytoplasm, ultimately triggering inflammasome activation. All results were reversed by the mutation in the METTL4 methyltransferase active site. Mettl4MUT-Apoe-/- mice showed suppressed mtDNA 6mA levels and atherosclerotic progression, and repaired mitochondrial function of macrophage, which were reversed by METTL4 restoration via bone marrow transplantation (n = 6). Pemetrexed (PEM) was identified as the first METTL4 antagonist to effectively alleviate atherosclerotic progression. Furthermore, we generated a proteolysis-targeting chimera drug based on PEM (PROTAC-PEM) that specifically targeting METTL4 in macrophages within plaques, showing a promising therapeutic effect on atherosclerosis. CONCLUSIONS: This study revealed a novel mechanism by which mtDNA 6mA orchestrated mitochondrial function-related gene expression in macrophages, thereby promoting atherosclerosis. Through various experimental techniques, such as gene manipulation, pharmacological inhibition and PROTAC, this study demonstrated that mtDNA 6mA and its specific enzyme METTL4 hold potential as therapeutic targets for atherosclerosis.

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Prevalent N6-methyldeoxyadenosine methylation in mammalian mitochondrial DNA

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