SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α
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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 approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha. In addition, SIRT1 and PGC-1alpha 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-1alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1alpha 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-1alpha 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-1alpha, a coactivator that regulates cellular metabolism.
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SIRT-1 is a key regulatory factor in muscle metabolism.
“SIRT-1 is a key regulatory factor in muscle metabolism.”
From GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway (2023) · cites this paper as [51]
SIRT1 has been implicated in turnover of defective mitochondria by mitophagy, in addition to its role in promoting mitochondrial biogenesis.
“In apparent contrast with its role in promoting mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ co-activator 1α deacetylation19–21, SIRT1 has also been implicated in turnover of defective mitochondria by mitophagy22,23.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [20]
The interaction between PGC-1α and SIRT1 suggests a role for SIRT1 in exercise-induced mitochondrial biogenesis.
“The interaction between PGC-1α and SIRT1 also suggests a role for SIRT1 in exercise-induced mitochondrial biogenesis [89].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [89]
PGC-1α activity is inhibited by GCN5 acetylation and stimulated by SIRT1 deacetylation.
“Activity of PGC-1α is regulated through inhibitory acetylation by GCN5 [59] and stimulatory deacetlyation by SIRT1 [60-62].”
From PGC-1α in aging and anti-aging interventions (2009) · cites this paper as [60]
AMPK and SIRT1 modulate directly PGC1α activity through phosphorylation and deacetylation respectively.
“AMPK and SIRT1, two major metabolic sensors in cells, modulate directly PGC1α activity through phosphorylation and deacetylation respectively”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Nemoto et al., 2005
AMPK and SIRT1 directly modulate PGC1alpha activity through phosphorylation and deacetylation, respectively.
“AMPK and SIRT1, the two mainmajor metabolic sensors in cells, modulate directly are direct modulators of PGC1α activity through phosphorylation and deacetylation respectively (Jager et al., 2007; Nemoto et al., 2005).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Nemoto et al., 2005
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- Authors
- Nemoto, S., Fergusson, M. M., & Finkel, T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Finkel, Toren
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 280
- Issue
- 16
- Pages
- 16456-16460
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2058768220
- Cited by
- 1,047
- References
- 35
- Citations by year
- 2026: 29 · 2025: 28 · 2024: 41 · 2023: 35 · 2022: 48 · 2021: 54 · 2020: 62 · 2019: 55 · 2018: 49 · 2017: 61 · 2016: 59 · 2015: 62 · 2014: 67 · 2013: 73 · 2012: 59
- FWCI
- 17.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SIRT1, PGC-1α, Sir2, NAD+-dependent deacetylase, ADP-ribosyltransferase, protein-protein interaction, mitochondrial biogenesis, oxygen consumption, cellular metabolism, lifespan extension, nicotinamide, P300, p53, FOXO3, sirtuins
- MeSH terms
- Forkhead Box Protein O1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Acetylation, Animals, DNA-Binding Proteins, HeLa Cells, Humans, NAD, Nerve Tissue Proteins, Niacinamide, Nuclear Proteins, Oxygen Consumption, Transcription Factors, Trans-Activators, Tumor Suppressor Protein p53, RNA-Binding Proteins, PC12 Cells, Sirtuins, E1A-Associated p300 Protein, Rats, Forkhead Transcription Factors, Sirtuin 1
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