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Myocardial mitochondrial dysfunction underlies the pathogenesis of heart failure (HF), but there are few treatment options to restore myocardial mitochondrial function. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a key role in regulating mitochondrial homeostasis. However, their relationship with HF is unclear.
2024年4月30日，空军军医大学陶凌团队在Circulation（IF 38）在线发表题为“Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure”的研究论文，该研究纠正线粒体DNA中METTL4介导的N6-甲基腺嘌呤过量可减轻心力衰竭。 METTL4主要定位于成人心肌细胞线粒体内。 mtDNA中的6mA修饰明显多于核DNA。 出生后心肌细胞成熟表现为mtDNA中6mA水平的降低，与METTL4表达的降低相一致。 然而，在衰竭的成人心肌细胞中观察到mtDNA 6mA水平和METTL4表达的增加，表明向新生儿样状态转变。 METTL4优先靶向mtDNA启动子区域，导致转录起始复合物组装干扰，mtDNA转录停滞，最终导致线粒体功能障碍。 通过METTL4过表达扩增心肌细胞mtDNA 6mA导致自发性线粒体功能障碍和HF表型。
The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-induced stress, revealing the stress response mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene abolishes mtDNA 6mA excess, preserves mitochondrial function, and mitigates HF development after continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and provided therapeutic remission to mice with pre-existing HF, regardless of whether the disease was caused by AngII/PE infusion or myocardial ischemia/reperfusion injury. The study found that cardiomyocyte mtDNA 6mA and the corresponding methyltransferase METTL4 play a key role in the pathogenesis of mitochondrial dysfunction and heart failure. Targeted inhibition of METTL4 to correct mtDNA 6mA excess is a promising strategy for developing mitochondria-centric HF interventions.
Mitochondria are the main powerhouses of adult cardiomyocytes, coordinating the synthesis of adenosine triphosphate and fueling the continuous cycle of myocardial contraction and relaxation In addition to playing a leading role in energy production, mitochondria also help regulate essential cellular processes, including calcium homeostasis, reactive oxygen species (ROS) production, and regulation of programmed cell death pathways, and thus occupy a central role in maintaining heart health and the pathogenesis of heart disease. Mitochondrial dysfunction can lead to a range of adverse effects, such as energy expenditure, oxidative stress, activation of maladaptive signaling cascades, and cardiomyocyte death, all of which together contribute to the progression of heart failure (HF). Mitochondria stand out among organelles with their unique characteristics: the presence of mitochondrial DNA (mtDNA), confirming that they come from the endosymbiotic ancestors of the once-free-living prokaryotes of the compact circular mtDNA genome encased in the mitochondrial matrix, encoding key proteins necessary for the construction of electron transport chains (ETCs), and precise transcription of mtDNA is essential for maintaining mitochondrial function as well as cellular energy homeostasis, given its central role in cellular metabolism. In order to fine-tune the activity of mitochondria according to the fluctuating energy needs of the cell and the physiological conditions of the organism, complex control systems have evolved, and the core of this regulation, which is controlled primarily by the nucleus, is the nuclear-encoded mitochondrial RNA polymerase (POLRMT), which works with key co-regulators, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M) The cooperative triplet initiates mtDNA transcription by forming a complex in the D-loop region containing the promoter, effectively controlling transcriptional mechanisms within the mitochondria. Recent studies have elucidated the key nature of this transcriptional control, linking perturbations in these processes to the pathogenesis of HF. However, the exact role and mechanism of mtDNA transcriptional dysregulation in HF remains under-characterized.
模式图（Credit: Circulation）
Epigenetic mechanisms play a key role in the regulation of gene expression, enabling organisms to exhibit phenotypic variation and respond adaptively to environmental changes without the need for changes in gene sequences. As early as the 70s of the 20th century, the discovery of C5-methylcytosine (5mC) modification in mitochondrial DNA proposed the concept of mitochondrial epigenetics or mitotic epigenetics. Recent studies have further expanded the understanding of mitochondrial epigenetic modifications, revealing that deoxyadenosine in mtDNA can be methylated to 6 mA by METTL4 (methyltransferase-like protein 4), suggesting that 6 mA is another methylation in mtDNA in addition to 5 mC. The effects of mtDNA methylation on mitochondrial function are profound, especially since they are implicated in the pathogenesis of various diseases. Despite significant advances, the specific role of mtDNA methylation in mitochondrial biology and its impact on heart health and disease remains an area of limited understanding. Taken together, this study suggests that the p53-METTL4-mtDNA 6mA axis regulates mtDNA transcription, cardiac mitochondrial function, and HF occurrence when eliciting HF stress, such as AngII/PE and myocardial ischemia/reperfusion. Targeting METTL4 to correct mtDNA 6mA excess can improve myocardial mitochondrial and cardiac performance, providing a new avenue for HF intervention. These results highlight the importance of mtDNA 6mA and its methyltransferase METTL4 in regulating cardiac mitochondrial homeostasis, suggesting that they could serve as potential targets for the development of mitochondria-focused cardiac therapeutics.
Original link https://doi.org/10.1161/CIRCULATIONAHA.123.068358
Editor-in-charge|Explore Jun
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文章来源|“ iNature”
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