The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation.

After birth, the heart undergoes a shift in energy metabolism and cytoarchitecture to enhance efficient energy production and cardiac contraction, which is essential for postnatal development and growth. However, the precise mechanisms regulating this process remain elusive. Here we show that the RNA modification enzyme Mettl1 is a critical regulator of postnatal metabolic reprogramming and cardiomyocyte maturation in mice, primarily through its influence on the translation of the rate-limiting ketogenesis enzyme Hmgcs2. Our findings reveal that ketogenesis is vital for the postnatal transition of fuel from glucose to fatty acids in cardiomyocytes, achieved by modulating tricarboxylic acid cycle-related enzymatic activity via lysine β-hydroxybutyrylation protein modification. Loss of Mettl1 results in aberrant metabolic reprogramming and cardiomyocyte immaturity, leading to heart failure, although some clinical features can be rescued by β-hydroxybutyrate supplementation. Our study provides mechanistic insights into how Mettl1 regulates metabolic reprogramming in neonatal cardiomyocytes and highlights the importance of ketogenesis in cardiomyocyte maturation.