Loss of NAT10 Reduces the Translation of mRNA Through ac4C Modification in Cardiomyocytes and Induces Heart Failure.

BACKGROUND

In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4-acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N-acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology.

METHODS AND RESULTS

Cardiac-specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by in vitro data. Activation of the signaling pathway was closely associated with enhanced apoptosis in NAT10-deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome-wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of in cardiomyocytes recapitulated the phenotype of NAT10 deficiency, including increased cardiomyocyte apoptosis and activated signaling. Finally, overexpression of rescued cardiomyocyte apoptosis and activation induced by NAT10 inhibition.

CONCLUSIONS

Our study highlights the significance of NAT10 in cardiomyocyte physiology, demonstrating that NAT10 loss is sufficient to induce cardiomyocyte apoptosis and heart failure. NAT10 regulates the translational efficiency of , a key mediator, through mRNA ac4C modification during heart failure.