METTL4 is a dual-specificity N6-adenine methyltransferase that catalyzes methylation of both RNA and DNA substrates. Its primary RNA function involves catalyzing N6,2'-O-dimethyladenosine (m6Am) formation at position 30 of U2 small nuclear RNA (snRNA), which regulates pre-mRNA splicing by affecting splice site recognition and exon inclusion 1. METTL4 also acts as a mitochondrial DNA N6-methyldeoxyadenosine (6mA) methyltransferase, with mammalian mtDNA containing approximately 1,300-fold higher 6mA levels than genomic DNA 2. Mechanistically, METTL4-mediated mtDNA 6mA methylation represses mitochondrial gene transcription by inhibiting TFAM DNA-binding and reducing mtDNA copy number, leading to mitochondrial dysfunction 2. This mitochondrial dysfunction involves disruption of complex V activity and subsequent inflammasome activation through cytoplasmic mtDNA release 3. Disease relevance includes roles in atherosclerosis, where METTL4 expression is elevated in plaque macrophages and promotes inflammatory responses 3, hypertensive chr18 kidney disease through tubular epithelial cell mitochondrial dysfunction 4, and liver fibrosis via ferroptosis regulation 5. Clinically, METTL4 represents a potential therapeutic target, with antagonists like pemetrexed showing promise in treating atherosclerosis 3.