SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α*

By S. Nemoto, M. Fergusson, Toren Finkel. Journal of Biological Chemistry, 2005

1,068 citations recorded by the source corpus.

In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by ∼25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1α. In addition, SIRT1 and PGC-1α directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1α but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1α is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1α deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1α, a coactivator that regulates cellular metabolism.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/994502878b52d8830532a9617f0ea6c2a4d86ce6

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Citations in the corpus

The world of protein acetylation. (2016, background): “Acetylation by GCN5 renders this transcription factor inactive [340], while it is deacetylated by Sirt1 [341,342].”
A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine (2005, background): “PC12 cells that overexpress SIRT1 experience a 25% reduction in oxygen utilization (161).”
Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “However, in a neuronal cell line, overexpression of SIRT1 decreases the activity of PGC1- and mitochondrial function (Nemoto et al. 2005), suggesting that the relationship between SIRT1 and PGC-1 may be complex.”
Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. (2006, background): “…that the consequence of RSV activation of SIRT1 is different in other tissues, since unlike the stimulation of PGC-1a activity seen here in muscle and previously reported in liver (Rodgers et al., 2005), in the PC12 adrenal cell line, PGC-1a activity was inhibited by SIRT1 (Nemoto et al., 2005).”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “The authors showed that SIRT1 interacts with and deacetylates PGC-1 in a NAD -dependent manner (230, 275).”
The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “demonstrated that SIRT1 regulates acetylation of PGC-1a, a master regulator of mitochondrial biogenesis (111).”
Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. (2008, background): “[PubMed: 17983582] Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.”
Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging (2009, background): “Sirt1 is known to activate PGC-1 by deacetylation (29), and while the detailed mechanisms of this feedback regulation remain unclear, our findings suggest that Sirt1/PGC-1 form a regulatory axis to control mitochondrial function during aging.”
A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy (2008, background): “The HA-tagged Sirt1 wild-type or deacetylase-inactive mutant (HY) and myc-Sirt3 have been described (32).”
Transcriptional control of mitochondrial biogenesis and function. (2009, background): “Finally, the effects of SIRT1 on PGC-1α may depend on cellular context because SIRT1 represses PGC-1α activity in PC12 cells (162).”