The study investigates the functional interaction between SIRT1, a NAD-dependent deacetylase, and PGC-1α, a transcriptional coactivator involved in mitochondrial biogenesis. Overexpression of SIRT1 in PC12 cells reduces cellular oxygen consumption by approximately 25%. SIRT1 and PGC-1α directly interact and can be co-immunoprecipitated. A single amino acid mutation in the ADP-ribosyltransferase domain of SIRT1 inhibits this interaction but does not affect its interaction with p53 or Foxo3a. PGC-1α is acetylated in vivo, and this acetylation is increased by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. SIRT1 catalyzes PGC-1α deacetylation both in vitro and in vivo. These findings suggest a direct link between sirtuins and PGC-1α, potentially mediating the anti-aging effects of sirtuins and coordinating metabolic decisions with metabolic status.The study investigates the functional interaction between SIRT1, a NAD-dependent deacetylase, and PGC-1α, a transcriptional coactivator involved in mitochondrial biogenesis. Overexpression of SIRT1 in PC12 cells reduces cellular oxygen consumption by approximately 25%. SIRT1 and PGC-1α directly interact and can be co-immunoprecipitated. A single amino acid mutation in the ADP-ribosyltransferase domain of SIRT1 inhibits this interaction but does not affect its interaction with p53 or Foxo3a. PGC-1α is acetylated in vivo, and this acetylation is increased by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. SIRT1 catalyzes PGC-1α deacetylation both in vitro and in vivo. These findings suggest a direct link between sirtuins and PGC-1α, potentially mediating the anti-aging effects of sirtuins and coordinating metabolic decisions with metabolic status.