SIRT1, a mammalian ortholog of the NAD-dependent deacetylase Sir2, interacts with PGC-1α, a coactivator that regulates mitochondrial biogenesis and metabolism. Overexpression of SIRT1 in PC12 cells reduces oxygen consumption by approximately 25%. SIRT1 directly interacts with PGC-1α and can co-immunoprecipitate it as a molecular complex. A mutation in the ADP-ribosyltransferase domain of SIRT1 inhibits its interaction with PGC-1α but not with p53 or Foxo3a. PGC-1α is acetylated in vivo, and this acetylation is increased by treatment with nicotinamide or expression of p300. SIRT1 catalyzes PGC-1α deacetylation both in vitro and in vivo. These findings establish a direct link between sirtuins and PGC-1α, suggesting that SIRT1 regulates PGC-1α activity and acetylation, which in turn affects mitochondrial metabolism and oxygen consumption. The results indicate that SIRT1 may play a role in aging by modulating mitochondrial function and metabolic processes. The interaction between SIRT1 and PGC-1α is distinct from their interactions with other proteins like p53 or Foxo3a. SIRT1's activity is regulated by NAD levels, and its interaction with PGC-1α may help coordinate metabolic status with gene expression. The study highlights the importance of SIRT1 in regulating cellular metabolism and aging through its interaction with PGC-1α.SIRT1, a mammalian ortholog of the NAD-dependent deacetylase Sir2, interacts with PGC-1α, a coactivator that regulates mitochondrial biogenesis and metabolism. Overexpression of SIRT1 in PC12 cells reduces oxygen consumption by approximately 25%. SIRT1 directly interacts with PGC-1α and can co-immunoprecipitate it as a molecular complex. A mutation in the ADP-ribosyltransferase domain of SIRT1 inhibits its interaction with PGC-1α but not with p53 or Foxo3a. PGC-1α is acetylated in vivo, and this acetylation is increased by treatment with nicotinamide or expression of p300. SIRT1 catalyzes PGC-1α deacetylation both in vitro and in vivo. These findings establish a direct link between sirtuins and PGC-1α, suggesting that SIRT1 regulates PGC-1α activity and acetylation, which in turn affects mitochondrial metabolism and oxygen consumption. The results indicate that SIRT1 may play a role in aging by modulating mitochondrial function and metabolic processes. The interaction between SIRT1 and PGC-1α is distinct from their interactions with other proteins like p53 or Foxo3a. SIRT1's activity is regulated by NAD levels, and its interaction with PGC-1α may help coordinate metabolic status with gene expression. The study highlights the importance of SIRT1 in regulating cellular metabolism and aging through its interaction with PGC-1α.