SIRT6-Mediated Regulation of TFAM: A Central Mechanism Connecting Nuclear and Mitochondrial Transcriptional Processes and Mitophagy

Nuclear and mitochondrial transcriptional regulation represent distinct mechanisms of gene expression control, both of which have garnered significant scientific attention. However, the interplay between these two regulatory processes remains poorly understood and underexplored. Our research uncovers a novel link between nuclear and mitochondrial transcription by identifying SIRT6 as an upstream regulator of the mitochondrial transcription factor TFAM, acting both indirectly and directly. Mechanistically, SIRT6 deacetylates FoxA1 at the K267 site, blocks the binding of FoxA1 to the promoter region of TFAM, leading to reduced TFAM expression. In parallel, SIRT6 translocates to the mitochondria and directly deacetylates TFAM at the K154 site, suppressing its transcriptional activity. Furthermore, SIRT6 downregulates the expression level of mitochondrial genes and proteins, inducing mitochondrial dysfunction and mitophagy by targeting TFAM. Additionally, TFAM promotes the growth and metastasis of colon cancer <i>in vitro</i> and <i>in vivo</i>, while SIRT6 was inhibited. In conclusion, our findings provide compelling evidence that SIRT6 establishes a network linking nuclear and mitochondrial transcription through the regulation of TFAM, identifying TFAM as a potential therapeutic target for cancer.