Aging Enzyme FTO Drives Atrial Fibrillation by Silencing a Key Potassium Channel Gene

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence rises sharply with age. Despite this well-known association, the molecular mechanisms linking the biology of aging to atrial electrical instability have remained poorly understood. This study identifies a novel epitranscriptomic pathway—centered on the RNA demethylase FTO and its target gene KCNE1—that causally connects aging-induced changes in RNA modification to increased AF susceptibility.

Using male mice across a range of ages (2–24 months), the researchers demonstrated that AF inducibility via programmed electrical stimulation first appeared at 19 months and became more pronounced by 24 months. Optical mapping revealed progressively heterogeneous conduction, shortened action potential duration (APD90), and increased APD30/80 ratios in aging animals, along with left atrial dilation and fibrosis. The investigators then profiled RNA modifications in atrial tissue and found that N6-methyladenosine (m6A)—the most abundant internal mRNA modification—was significantly reduced in 19-month-old mice. m6A sequencing identified 2,362 hypo-methylated peaks in aging atria, predominantly in exon and 3′UTR regions. Cross-referencing m6A-seq with mRNA-seq data, the team narrowed 42 co-downregulated genes to a single ion channel–relevant target: Kcne1, the regulatory beta-subunit of the IKs potassium channel complex. MeRIP-qPCR confirmed a 10-fold reduction in Kcne1 m6A methylation and a 4-fold reduction in Kcne1 mRNA in aging atria. Protein levels of Kcne1 were also markedly reduced, while its channel partner Kcnq1 and related subunit Kcne2 were unchanged. Patch-clamp recordings confirmed enhanced IKs current density in aging atrial cardiomyocytes, consistent with paradoxical gain-of-function when the inhibitory subunit Kcne1 is lost.

To establish causality, AAV9-mediated cardiomyocyte-specific Kcne1 knockdown in young (2-month-old) mice recapitulated the aging phenotype: increased AF inducibility, conduction heterogeneity, shortened APD, and enhanced IKs currents. Conversely, cardiomyocyte-specific Fto knockout in aging (19-month-old) mice restored Kcne1 mRNA and protein, normalized IKs current, and markedly reduced AF susceptibility—without affecting global cardiac function. Overexpression of wild-type Fto (but not a catalytically inactive mutant) in young mice reduced Kcne1 expression and increased AF inducibility, confirming that Fto's demethylase activity is required for its arrhythmogenic effect.

The team further explored why Fto accumulates during aging. They found that prostaglandin E2 (PGE2), which accumulates in aging cardiomyocytes, blocks proteasomal degradation of Fto protein, leading to its buildup. In iPSC-derived human atrial cardiomyocytes, FTO-mediated KCNE1 demethylation was shown to impair three post-transcriptional steps: pre-mRNA splicing, mRNA nuclear export, and translational efficiency. Finally, the negative correlation between FTO and KCNE1 expression was confirmed in left atrial appendage samples from human AF patients, strengthening the translational relevance of these findings.

Collectively, this work establishes a mechanistic axis in which aging-induced PGE2 accumulation stabilizes FTO → elevated FTO demethylates Kcne1 mRNA → reduced Kcne1 protein disinhibits IKs current → shortened atrial APD → increased AF vulnerability. These findings position the FTO-KCNE1-IKs axis as a promising therapeutic target for age-related AF.