SIRT3 Protein, Human

SIRT3, a NAD-dependent protein deacetylase, intricately modulates the acetylation status of key lysine residues in various mitochondrial target proteins, including ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA, and ATP synthase subunit ATP5PO. By catalyzing deacetylation, SIRT3 actively participates in the regulation of cellular energy metabolism, exerting influence on tissue-specific ATP levels and contributing to the fine-tuning of metabolic responses. Under metabolic stress conditions, SIRT3 deacetylates the transcription factor FOXO3, recruiting both FOXO3 and mitochondrial RNA polymerase POLRMT to mitochondrial DNA, thereby enhancing mtDNA transcription. Additionally, SIRT3 plays a crucial role in ceramide metabolism by deacetylating ceramide synthases CERS1, CERS2, and CERS6, promoting mitochondrial ceramide accumulation. Furthermore, SIRT3 regulates hepatic lipogenesis by utilizing NAD(+) substrate imported by SLC25A47, triggering downstream activation of the PRKAA1/AMPK-alpha signaling cascade. This activation ultimately leads to the downregulation of sterol regulatory element-binding protein (SREBP) transcriptional activities, mitigating ATP-consuming lipogenesis and restoring cellular energy balance.