BACKGROUND: The 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. METHODS: Slc25a26 knockout and cardiac-specific conditional knockout mouse models were generated to explore its function in vivo. Reconstructed adeno-associated virus was used to overexpress Slc25a26 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 biology in 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). RESULTS: We 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 of Slc25a26 causes embryonic lethality. Cardiac-specific deletion of Slc25a26 causes 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. CONCLUSIONS: These 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.

The authors have declared no competing interest.

This work was supported by grants from National Key R&D Program of China (2022YFA1104500 to LW and ZW), National Natural Science Foundation of China (82370392, 82070231 and 81722007 to ZW), CAMS Innovation Fund for Medical Sciences (2023-I2M-1-003 and 2022-I2M-2-001 to LW and ZW), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320026 to LW and ZW), National High Level Hospital Clinical Research Funding (2022-GSP-GG-7 to LW and ZW), Shenzhen Medical Research Fund (B2302026 to ZW), Shenzhen Fundamental Research Program (ZDSYS20200923172000001 to ZW), and Science, Technology and Innovation Commission of Shenzhen Municipality (RCJC20210706091947009 to ZW; RCBS20221008093333076 to NG).

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