心脏纤维化 z-bio 2025-05-16 3719

　　#Cardiac fibrosis (CF) is a common pathological basis of cardiovascular diseases such as heart failure and atrial fibrillation, characterized by abnormal proliferation and migration of myocardial fibroblasts and collagen deposition, ultimately leading to heart failure. Although this disease is prevalent globally, its specific mechanism is not yet fully understood.

　　In March of this year, Professor Tao Hui's team from the Second Affiliated Hospital of Anhui Medical University, together with Professor Zhao Jianyuan and Professor Zhang Ye's team from the Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, published a study titled "SLC31A1 loss depletion mitochondrial copper and promotes cardiac fibrosis" in the European Heart Journal. For the first time, the study systematically revealed a new mechanism of # mitochondrial copper depletion driving cardiac fibrosis through glycolysis reprogramming and # m6A epigenetic pathway, providing a breakthrough theoretical basis for the prevention and treatment of CF.

　　The article is co authored by Tu Bin and Song Kai, master's students from the Second Affiliated Hospital of Anhui Medical University, and Zhou Zeyu, postdoctoral fellow at the School of Medicine of Shanghai Jiao Tong University. Let's take a look at how this article integrates three major natural hotspots: mitochondrial copper depletion, glycolysis, and epigenetics (m6A).

　　Research Background and Scientific Issues

　　Copper is an essential trace element for the human body, involved in various physiological processes such as energy metabolism and antioxidant activity. Previous studies have found that abnormal copper metabolism is associated with cancer, diabetes and other diseases, but its role in heart fibrosis is still unclear. Researchers noticed that copper content in heart tissue was significantly reduced in patients with cardiac fibrosis and mouse models, and the expression of the gene SLC31A1 responsible for copper transport was also significantly decreased. This suggests that copper metabolism imbalance may be closely related to the occurrence of cardiac fibrosis.

　　Mitochondrial copper depletion: a key driver of cardiac fibrosis

　　Clinical and animal model validation

　　The research team found through inductively coupled plasma mass spectrometry (ICP-MS) that copper ion content was significantly reduced and copper transporter SLC31A1 expression was downregulated in Ang II/ISO induced mouse CF models, myocardial infarction models, and heart tissues of atrial fibrillation patients. Fluorescence probe tracing showed that abnormal distribution of mitochondrial copper was directly related to mitochondrial morphological fragmentation and reduced cristae count, suggesting that mitochondrial copper metabolism disorder is an early event in CF.

　　In vitro experiments have shown that Ang II stimulation of cardiac fibroblasts can lead to a decrease in mitochondrial membrane potential, a decrease in oxygen depletion rate (OCR), an increase in extracellular acidification rate (ECAR), and a significant increase in the expression of key glycolytic enzymes HIF-1 α and HK3. Knocking down SLC31A1 further exacerbates mitochondrial copper depletion, promotes fibroblast proliferation and collagen deposition; Overexpression of SLC31A1 or supplementation of copper ions reversed this process, confirming that mitochondrial copper depletion promotes CF by driving glycolytic reprogramming.

　　M6A epigenetic regulatory network: molecular mechanism of SLC31A1 inactivation

　　DNA methylation and transcriptional repression

　　Mechanism studies have found that there are typical CpG islands in the SLC31A1 promoter region, and their methylation levels are significantly elevated in CF models and atrial fibrillation patients. Methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP) experiments have confirmed that the methylated CpG binding protein MeCP2 inhibits transcription of SLC31A1 by recognizing its methylation site in the promoter, leading to copper transport dysfunction.

　　Upstream regulatory effect of m6A modification

　　Through m6A sequencing and RNA binding protein analysis, the team found that YTHDF1, as an m6A reader, specifically recognizes the m6A modification site of MeCP2 mRNA, enhances its stability, and promotes translation. Knocking down YTHDF1 can reduce MeCP2 expression, restore SLC31A1 transcription, and reverse mitochondrial copper depletion and CF phenotype. Clinical sample validation shows that the elevated expression of YTHDF1/MeCP2 in the heart tissue of atrial fibrillation patients is positively correlated with SLC31A1 methylation, further confirming the core role of the YTHDF1/MeCP2/m6A pathway in CF.

　　The research team also verified the above mechanism in tissue samples of patients with atrial fibrillation (AF) and diabetes cardiomyopathy (DCM). There is also a decrease in copper content, a decrease in SLC31A1 expression, and an increase in MeCP2/YTHDF1 levels in the heart tissue of these patients. This suggests that regulating copper metabolism and SLC31A1 may become a new strategy for treating cardiac fibrosis.

　　Can copper supplementation become a therapy?

　　Although copper supplementation may seem intuitive, research has found that the effect of copper supplementation alone is limited in the absence of SLC31A1. Therefore, future research can focus on how to restore the function of SLC31A1 through gene therapy or epigenetic drugs such as DNA demethylating agents. In addition, exploring inhibitors of the YTHDF1/MeCP2 pathway may also open up new avenues for clinical intervention.

　　This study innovatively integrates mitochondrial copper metabolism, glycolysis reprogramming, and m6A epigenetics, revealing a novel molecular network of cardiac fibrosis. Its scientific value lies not only in elucidating the dual role of SLC31A1 in cardiovascular disease, but also in confirming for the first time that m6A modification participates in organ fibrosis by regulating metal homeostasis, opening up new directions for cardiovascular epigenetics research.

　　In the future, precise intervention targeting the YTHDF1/MecP2/SLC31A1 axis is expected to become a key breakthrough point in reversing cardiac fibrosis and improving the prognosis of atrial fibrillation.