May 22, 2025
Directly Connecting DNA Epigenetic Player with Mitochondrial Metabolism via RNA Binding
DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation
In a recent issue of Molecular Cell, Prof. Guoping Fan from Scintillon Institute together with colleagues at UCLA and ShanghaiTech University published an article titled “DNA methyltransferase 1 modulates mitochondrial function through bridging m5C RNA methylation”.
Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are often accompanied by energy metabolism disorders and mitochondrial dysfunction. In recent years, the role of epigenetic regulatory mechanisms, especially DNA and RNA methylation, in these diseases has gradually attracted attention. DNA methyltransferase 1 (DNMT1), as an important enzyme for maintaining DNA methylation, has long been reported to function in development and disease, but its high expression in non-dividing neurons suggests that it may have unrevealed functions. At the same time, m5C methylation modification on RNA has also been found to be involved in regulating mRNA stability and translation efficiency, and is associated with a variety of neurological diseases. However, whether there is a direct connection between DNA methylation and RNA modification, and how this connection affects cell metabolism and nervous system function, remains an unknown area.
In this Molecular Cell paper, the research team found a new mechanism of DNA methyltransferase 1 (DNMT1) in regulating mitochondrial function and neurodegenerative diseases. DNMT1 is considered to be mainly responsible for maintaining the DNA methylation state and ensuring the stability of gene expression. This study revealed that DNMT1 can bind to mRNA extensively through the eCLIP-seq experimental system, indicating that it has the function of RNA binding protein. Further analysis found that DNMT1 can recruit NOP2/Sun RNA methyltransferase 2 (NSUN2) to promote the m5C modification of its bound transcripts, thereby enhancing the stability of these mRNAs closely related to mitochondrial metabolism, thereby regulating mitochondrial function.
To further study this new function of DNMT1 and its relationship with neurological diseases, the research team constructed transgenic mice carrying ADCA-DN (ataxia-deafness-narcolepsy syndrome)-related mutations (DNMT1 p.Ala560Val, A560V). The A560V mutation is located in the RFTS (Replication Foci Targeting Sequence) domain of the self-inhibitory domain of the DNMT1 protein. This mutation can affect the normal function of the RFTS domain, resulting in the failure of the self-inhibitory mechanism of DNMT1. This in turn enhances the ability of DNMT1 to bind to RNA, leading to abnormal stability and overexpression of metabolism-related mRNA, triggering mitochondrial oxidative stress, energy imbalance and a variety of neurodegenerative phenotypes. In an attempt to alleviate these phenotypes, the researchers used DNMT1 inhibitors and found that they could significantly alleviate the oxidative stress and ATP deficiency caused by the mutation, suggesting that regulating DNMT1-RNA interactions may be a potential strategy for treating mitochondrial-related neurological diseases.
Identification of a role of DNMT1, traditionally known for DNA methylation, in regulating mitochondrial health through RNA modification. Their findings explain how the mutation in DNMT1 disrupts cellular energy metabolism, contributing to neurological disorders, and suggest therapeutic potential targeting RNA methylation in neurodegenerative diseases.