BACKGROUNDThe heart undergoes hypertrophy as a compensatory mechanism to cope with increased hemodynamic stress, and it can transition into a primary driver of heart failure. Pathological cardiac hypertrophy is characterized by excess protein synthesis. Protein translation is an energy-intensive process that necessitates an inherent mechanism to flexibly fine-tune intracellular bioenergetics according to the translation status; however, such a molecular link remains lacking.METHODSSlc25a26knockout and cardiac-specific conditional knockout mouse models were generated to explore its functionin vivo. Reconstructed adeno-associated virus was used to overexpressSlc25a26 in vivo. Cardiac hypertrophy was established by transaortic constriction (TAC) surgery. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of SLC25A26 in cardiomyocyte growth and mitochondrial biologyin vitro. RNA sequencing was conducted to explore the regulatory mechanism by SLC25A26. m1A-modified tRNAs were profiled by RNA immuno-precipitation sequencing. Label-free proteomics was performed to profile the nascent peptides affected by S-adenosylmethionine (SAM).RESULTSWe show that cardiomyocytes are among the top cell types expressing the SAM transporter SLC25A26, which maintains low-level cytoplasmic SAM in the heart. SAM biosynthesis is activated during cardiac hypertrophy, and feedforwardly mobilizes the mitochondrial translocation of SLC25A26 to shuttle excessive SAM into mitochondria. Systemic deletion ofSlc25a26causes embryonic lethality. Cardiac-specific deletion ofSlc25a26causes spontaneous heart failure and exacerbates cardiac hypertrophy induced by transaortic constriction. SLC25A26 overexpression, both before or after TAC surgery, rescues the hypertrophic pathologies and protects from heart failure. Mechanistically, SLC25A26 maintains low-level cytoplasmic SAM to restrict tRNA m1A modifications, particularly at A58 and A75, therefore decelerating translation initiation and modulating tRNA usage. Simultaneously, SLC25A26-mediated SAM accumulation in mitochondria maintains mitochondrial fitness for optimal energy production.CONCLUSIONSThese findings reveal a previously unrecognized role of SLC25A26-mediated SAM compartmentalization in synchronizing translation and bioenergetics. Targeting intracellular SAM distribution would be a promising therapeutic strategy to treat cardiac hypertrophy and heart failure.Clinical PerspectiveWhat Is New?An activation of S-adenosylmethionine (SAM) biosynthesis during cardiac hypertrophy boosts a feed-forward mitochondrial translocation of its transporter SLC25A26 to shuttle excessive SAM into mitochondria.SLC25A26-mediated cytoplasmic SAM containment restricts translation through inhibiting TRMT61A-mediated tRNA m1A modifications, particularly at A58 and A75, which modulates translation initiation and codon usage.SLC25A26-mediated mitochondrial SAM accumulation enhances mtDNA methylation and is required for the implement of mitochondrial fission and mitophagy, therefore maintaining optimal bioenergetics.Cardiac-specific knockout ofSlc25a26causes spontaneous heart failure, and exacerbates transaortic constriction (TAC)-induced cardiac hypertrophy, while its overexpression rescues the hypertrophic pathologies.What Are the Clinical Implications?Cardiomyocyte-specific expression of SLC25A26 maintains low-level cytoplasmic SAM and contributes to the relatively low protein synthesis rate in the heart.Targeting intracellular SAM distribution would be a promising therapeutic strategy to treat cardiac hypertrophy and heart failure.
