Rectifying METTL4-Mediated N 6 -Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure

作者：Fuyang Zhang, Ling Zhang, Guangyu Hu, Xiyao Chen, Hui Liu, Congye Li, Xiong Guo, Chong Huang, Fangfang Sun, Tongzheng Li, Zhe Cui, Yongzhen Guo, Wenjun Yan, Yunlong Xia, Zhiyuan Liu, Zhen Lin, Weixun Duan, Linhe Lu, Xinyi Wang, Zhengyang Wang, Shan Wang, Ling Tao · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.068358 · 被引用次数：42 · 研究领域：Mitochondrial Function and Pathology、RNA modifications and cancer、GDF15 and Related Biomarkers

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N 6 -methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like sta...