GRSF1 is a mitochondrial and nuclear RNA-binding protein that regulates post-transcriptional gene expression by binding G-rich RNA sequences and G-quadruplex structures. It promotes assembly of the mitochondrial ribosome and recruits mitochondrial mRNAs and long non-coding RNAs, particularly those transcribed from the light strand of mtDNA including ND6 mRNA and transcripts encoding MT-CYB and MT-ND5 123. GRSF1 also facilitates degradation of non-coding mitochondrial transcripts by unwinding G-quadruplex structures, allowing access by the degradosome 3. Beyond mitochondrial biogenesis, GRSF1 regulates cellular metabolism and homeostasis. In cardiac tissue, GRSF1 maintains branched-chain amino acid balance by stabilizing BCKDHB mRNA, and GRSF1 downregulation is observed in patients with heart failure and dilated cardiomyopathy; cardiomyocyte-specific GRSF1 deletion causes cardiac dysfunction and heart failure, while overexpression attenuates disease progression 4. GRSF1 also suppresses hypercoagulability during aging by reducing fibrinogen mRNA stability 5 and antagonizes cellular senescence by maintaining mitochondrial function and limiting ROS production and DNA damage 6. Beyond mitochondrial functions, GRSF1 facilitates nuclear export and translation of influenza A virus mRNAs 7. These findings identify GRSF1 as a multifunctional metabolic checkpoint with therapeutic potential for heart failure and age-related diseases.