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SLC25A26-mediated subcellular SAM redistribution alleviates cardiac hypertrophy by coordinating translation and bioenergetics
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DOI：10.1016/j.gendis.2026.102379.png)
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Abstract
En 中文
Protein synthesis is an energy-intensive process. Cardiac hypertrophy is characterized by both excess protein synthesis and mitochondrial defects; however, the mechanisms underpinning proteostatic imbalance and bioenergetic failure remain unclear. We found that phosphorylation of MAT2A at S384 during cardiac hypertrophy enhanced S-adenosylmethionine (SAM) biosynthesis, which mobilized mitochondrial translocation of its transporter SLC25A26 in a feedforward manner. Cardiac-specific Slc25a26 deletion led to spontaneous heart failure and exacerbated cardiac hypertrophy induced by transaortic constriction. Transcriptome analysis revealed specific regulations of ribosome and tRNA synthase pathways after Slc25a26 deficiency. Ribosome profiling demonstrated a pro-hypertrophic translatome reprogramming in Slc25a26-deficient hearts. Puromycin incorporation assays showed that protein synthesis rate was promoted by Slc25a26 deficiency, but was suppressed by its overexpression in cardiomyocytes. Mechanistically, Slc25a26 deficiency augmented cytoplasmic SAM contents, resulting in enhanced tRNA m1A modification, particularly at A58. m1A58 modification on tRNAiMet accelerated translation initiation. Silencing methyltransferase Trmt61a or demethylases Alkbh1/3 blunted the translational regulations by Slc25a26 knockdown or overexpression, respectively. Moreover, Slc25a26 deficiency diminished mitochondrial SAM import, resulting in impairments of mitochondrial fitness and bioenergetics. Finally, post-transaortic constriction Slc25a26 gene therapy significantly rescued hypertrophic pathologies. Our findings demonstrate a crucial role of SLC25A26-mediated subcellular SAM distribution in cardiac pathophysiology via coordinating translation and bioenergetics.
Keywords:
Cardiac hypertrophy
Mitochondrial fitness
SAM
Translation
tRNA methylation
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