Affinage

Showing PPARGC1A — PGC-1ALPHA is a alias.

PPARGC1A

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha · UniProt Q9UBK2

Length
798 aa
Mass
91.0 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPARGC1A (PGC-1α) is a transcriptional coactivator that orchestrates mitochondrial biogenesis and the broader cellular energy-metabolism program by inducing and directly coactivating nuclear transcription factors on target promoters (PMID:10412986). It drives the NRF-1/NRF-2 → mtTFA axis to stimulate mitochondrial DNA replication and respiration in muscle (PMID:10412986), and it acts through the orphan nuclear receptor ERRα as a recurrent partner to activate diverse metabolic targets including the mitochondrial pyruvate carrier MPC1, alanine aminotransferase ALT2, endothelial eNOS, and mitochondrial translation/supercomplex programs (PMID:29669911, PMID:29315328, PMID:27910955, PMID:37639610); it also enhances ERRγ transactivation via the receptor's AF-2 domain (PMID:12470660). Through PPARβ it transactivates a distal PPAR response element in the Ucp3 promoter to set oxidative capacity (PMID:31228206), and it supports peroxisomal biogenesis in brown fat and hepatic gluconeogenic and bile-acid (CYP7A1) programs (PMID:21059926, PMID:14522988). PGC-1α activity is set by an energy-sensing post-translational network: SIRT1 deacetylates it in an NAD+-dependent manner to selectively activate gluconeogenic (but not mitochondrial) genes, while protein abundance is controlled by EWS-dependent suppression of FBXW7-mediated ubiquitination and proteasomal degradation (PMID:15744310, PMID:25918410). Beyond core metabolism, PGC-1α couples tissue physiology to its transcriptional outputs: it induces muscle FNDC5/irisin to drive adipose browning and, in hippocampus, BDNF expression (PMID:22237023, PMID:24120943), regulates VEGFA-dependent retinal angiogenesis (PMID:23141926), promotes autophagy/mitophagy through SQSTM1 and the ULK1-ERRα axis (PMID:31441382, PMID:33771213), and controls extrasynaptic NMDAR activity and neuronal mitochondrial density (PMID:22593067, PMID:19542216). Its expression is itself repressed by the Notch effector Hes1, linking it to fatty-acid-oxidation defects and kidney fibrosis (PMID:28751525).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1999 High

    Established the founding mechanism by which PGC-1α builds mitochondria — defining it as a coactivator that both induces and directly binds nuclear respiratory factors to drive the mtTFA-dependent mitochondrial gene program.

    Evidence Overexpression in muscle cells with promoter/binding assays and mitochondrial function readouts

    PMID:10412986

    Open questions at the time
    • Did not map the post-translational signals that switch the coactivator on
    • Tissue-specific selectivity of NRF coactivation not addressed
  2. 1999 High

    Defined the human gene structure, chromosomal location, and broad tissue expression, framing PGC-1α as a metabolically active coactivator across energy-demanding organs.

    Evidence cDNA cloning, genomic organization, Northern blotting, chromosomal mapping

    PMID:10585775

    Open questions at the time
    • No functional or mechanistic data
    • Isoform diversity not characterized
  3. 2002 Medium

    Showed PGC-1α directly partners with the ERR family, identifying ERRγ as a coactivation target and mapping the receptor AF-2 domain requirement — a partnership that recurs across later metabolic programs.

    Evidence In vitro interaction, transfection reporter assays, receptor truncation mapping

    PMID:12470660

    Open questions at the time
    • Endogenous gene targets of the PGC-1α–ERRγ pair not defined
    • Single-lab in vitro context
  4. 2003 High

    Extended PGC-1α function into hepatic lipid/cholesterol catabolism by showing direct activation of the CYP7A1 promoter and bile-acid biosynthesis under fasting/diabetic conditions.

    Evidence Adenoviral overexpression in HepG2, promoter assays, bile-acid measurement, mouse models

    PMID:14522988

    Open questions at the time
    • Direct transcription-factor intermediary on the CYP7A1 promoter not pinned down
  5. 2005 High

    Revealed how nutrient status tunes coactivator activity — SIRT1 NAD+-dependent deacetylation selectively activates the gluconeogenic but not the mitochondrial branch of PGC-1α output.

    Evidence Co-IP, in vitro deacetylation, adenoviral gain/loss-of-function, hepatic glucose output

    PMID:15744310

    Open questions at the time
    • Acetyl-lysine residues conferring program selectivity not fully resolved
    • Counterbalancing acetyltransferase identity not addressed here
  6. 2006 Medium

    Tested whether PGC-1α drives gluconeogenesis through FOXO1 and showed FOXO1 is neither necessary nor sufficient, redefining their cooperation as indirect.

    Evidence G6Pase-luciferase reporter assays with FOXO1 gain/loss-of-function

    PMID:17024043

    Open questions at the time
    • The actual direct factor mediating gluconeogenic activation left open
    • Single reporter system
  7. 2009 Medium

    Demonstrated PGC-1α controls neuronal mitochondrial density and is the specific effector of SIRT1/GCN5 acetylation signaling in neurons, distinguishing its role from PGC-1β.

    Evidence Neuronal overexpression/shRNA epistasis, SIRT1 OE, GCN5 suppression, mitochondrial density

    PMID:19542216

    Open questions at the time
    • Downstream neuronal transcription factors not mapped
    • Single lab
  8. 2011 High

    Placed PGC-1α downstream of lipolysis-derived PPAR ligands in cardiac substrate oxidation, where its loss contributes to lethal cardiomyopathy rescued by PPARα agonism.

    Evidence ATGL knockout mice with PPARα agonist rescue, mitochondrial and cardiac function assays

    PMID:21857651

    Open questions at the time
    • Direct contribution of PGC-1α versus PGC-1β to the rescue not separated
  9. 2012 High

    Connected muscle PGC-1α to systemic endocrine signaling by identifying the FNDC5/irisin myokine that drives white-adipose browning and energy expenditure.

    Evidence Transgenic mice, cell culture, in vivo irisin treatment, metabolic measurement

    PMID:22237023

    Open questions at the time
    • The adipocyte irisin receptor not identified in this work
  10. 2012 High

    Expanded PGC-1α function to angiogenesis, showing it drives VEGFA expression required for retinal vessel development and pathological neovascularization.

    Evidence PGC-1α KO mice, oxygen-induced retinopathy, VEGFA expression, vascular morphometry

    PMID:23141926

    Open questions at the time
    • Transcription factor partner on the VEGFA promoter not defined
  11. 2012 High

    Identified a neuroprotective role distinct from bioenergetics — PGC-1α restrains extrasynaptic NMDAR activity and excitotoxicity, with shared mechanism in Huntingtin pathology.

    Evidence RNAi/overexpression in primary neurons, electrophysiology, excitotoxicity and mHtt epistasis

    PMID:22593067

    Open questions at the time
    • Molecular effector linking PGC-1α to NMDAR surface activity unknown
  12. 2013 High

    Extended the FNDC5/irisin axis to the brain, showing PGC-1α-dependent neuronal FNDC5 drives hippocampal BDNF expression.

    Evidence Pgc1a KO mice, primary neuron cultures, adenoviral OE, RNAi, gene expression

    PMID:24120943

    Open questions at the time
    • Mechanism by which FNDC5 induces BDNF not resolved
  13. 2014 High

    Identified IRF4 as a required transcriptional partner for the thermogenic UCP1 program, showing PGC-1α cannot drive thermogenesis without it.

    Evidence Reciprocal Co-IP, tissue-specific IRF4 KO/OE, energy expenditure and cold tolerance

    PMID:24995979

    Open questions at the time
    • Structural basis of the IRF4–PGC-1α interaction not defined
  14. 2015 High

    Established proteostatic control of PGC-1α abundance — EWS stabilizes the protein by suppressing FBXW7-mediated ubiquitination and degradation.

    Evidence EWS KO cells/mice, ubiquitination and proteasome assays, FBXW7 knockdown rescue

    PMID:25918410

    Open questions at the time
    • Degradation-targeting phosphodegron on PGC-1α not mapped here
  15. 2016 High

    Defined an endothelial protective program in which ERRα-dependent PGC-1α drives eNOS expression to guard against hypertension.

    Evidence Endothelial-specific KO/TG mice, angiotensin II, eNOS and ERRα genetic/pharmacologic epistasis

    PMID:27910955

    Open questions at the time
    • Direct ERRα binding site on the eNOS gene not shown
  16. 2017 High

    Showed PGC-1α expression is directly repressed by the Notch effector Hes1, mechanistically linking its suppression to fatty-acid-oxidation defects and kidney fibrosis.

    Evidence ChIP for Hes1 on the PGC-1α regulatory region, Notch1 transgenic mice, rescue by PGC-1α OE

    PMID:28751525

    Open questions at the time
    • Cofactors mediating Hes1 repression not identified
  17. 2017 Medium

    Revealed a non-canonical nucleolar role for PGC-1α — it associates with rDNA and boosts RNA Pol I/UBF recruitment, coupling ribosomal to mitochondrial biogenesis.

    Evidence Subcellular fractionation, rDNA ChIP for Pol I and UBF, cell and mouse models

    PMID:28819135

    Open questions at the time
    • Signal directing PGC-1α to the nucleolus unknown
    • Single lab
  18. 2018 Medium

    Mapped a direct PGC-1α–ERRα mechanism for mitochondrial pyruvate import via activation of the MPC1 promoter, required for pyruvate-dependent respiration.

    Evidence OE/siRNA, ERRα-response-element reporter, Co-IP, oxygen consumption with MPC inhibitor

    PMID:29669911

    Open questions at the time
    • Endogenous ERRα occupancy at the MPC1 locus not shown by ChIP
    • Single lab
  19. 2018 Medium

    Showed the PGC-1α–ERRα pair controls amino-acid metabolism by transactivating the ALT2 promoter to drive fasting alanine production.

    Evidence OE/knockdown in C2C12, ALT2 promoter reporter, alanine measurement

    PMID:29315328

    Open questions at the time
    • In vivo confirmation of the muscle alanine program limited
    • Single lab
  20. 2018 Medium

    Demonstrated PGC-1α/β increase muscle protein synthesis and myotube growth through ERRα, independently of the Akt/mTOR pathway.

    Evidence C2C12 OE with PI3K/mTOR inhibitors and ERRα siRNA, protein-synthesis and diameter readouts

    PMID:30356878

    Open questions at the time
    • Direct translational targets downstream of ERRα not defined
    • Single lab
  21. 2018 Medium

    Linked mutant p53 to PGC-1α in cancer, showing the codon 72 R72 variant enhances PGC-1α-driven mitochondrial function and metastatic capacity.

    Evidence Co-IP, migration/metastasis and mitochondrial assays, in vivo models

    PMID:29463573

    Open questions at the time
    • Mechanism of mutant-p53 modulation of PGC-1α activity not detailed
    • Single lab
  22. 2019 Medium

    Defined the PGC-1α/PPARβ axis as the direct driver of Ucp3 via a distal PPAR response element, with UCP3 essential for PGC-1α-induced oxidative capacity.

    Evidence Quantitative ChIP on the Ucp3 promoter, OE, PPARβ/UCP3 knockdown, oxidative capacity

    PMID:31228206

    Open questions at the time
    • Mechanism by which UCP3 supports oxidative capacity not resolved
    • Single lab
  23. 2019 Medium

    Showed PGC-1α sets the hepatic IRS1/IRS2 ratio downstream of glucagon/cAMP/CREB to control insulin-mediated suppression of gluconeogenesis.

    Evidence Reciprocal gain/loss-of-function in hepatocytes, ex vivo glucose production, in vivo OE

    PMID:30770439

    Open questions at the time
    • Direct CREB/PGC-1α occupancy at the IRS2 locus not shown
    • Single lab
  24. 2019 Medium

    Identified SQSTM1/p62 as a direct PGC-1α target driving vascular smooth muscle autophagy and limiting senescence.

    Evidence ppargc1a KO VSMCs, adenoviral OE, autophagy inhibitors, SQSTM1/ATG5 siRNA, EM, SA-β-gal

    PMID:31441382

    Open questions at the time
    • Direct promoter binding to SQSTM1 not demonstrated by ChIP
    • Single lab
  25. 2019 High

    Showed PGC-1α promotes fibroblast autophagy to enable TGFβ-driven myofibroblast differentiation and fibrosis, with pharmacological inhibition reversing established fibrosis.

    Evidence Fibroblast-specific KO mice, two fibrosis models, SR18292 inhibition, autophagy reporters

    PMID:32482644

    Open questions at the time
    • Direct autophagy gene targets in fibroblasts not enumerated
  26. 2020 Medium

    Distinguished PGC-1α isoform functions, showing isoform 4 uniquely drives anti-apoptotic programs in hepatocytes while canonical PGC-1α1 suppresses inflammatory networks.

    Evidence Isoform-specific gain/loss-of-function in hepatocytes, microarray, apoptosis assays, TNFα/LPS

    PMID:32180561

    Open questions at the time
    • Transcription factor partners distinguishing isoform-specific programs not defined
    • Single lab
  27. 2020 Medium

    Revealed a developmental role in zebrafish, where ppargc1a drives ciliogenesis and ciliated-cell fate through prostaglandin (ptgs1/PGE2) signaling.

    Evidence Zebrafish KO with PGE2 and ptgs1 rescue/epistasis, cilia imaging, renal MCC fate

    PMID:33176142

    Open questions at the time
    • Mammalian conservation of the ciliogenic role not tested here
    • Single lab, zebrafish model
  28. 2021 Medium

    Defined a microglial PGC-1α–ERRα–ULK1 axis promoting autophagy/mitophagy that limits NLRP3 inflammasome activation after ischemic stroke.

    Evidence Microglia-specific TG mice, MCAO, ChIP-Seq, ULK1 inhibition/knockdown, NLRP3/autophagy readouts

    PMID:33771213

    Open questions at the time
    • Direct ERRα-dependent occupancy at ULK1 not isolated from ChIP-Seq
    • Single lab
  29. 2021 Medium

    Implicated PGC-1/PPAR signaling in cardiomyocyte maturation through previously unrecognized downstream proteins YAP1 and SF3B2, active in vivo but not in iPSC-derived cardiomyocytes.

    Evidence Single-cell transcriptomics, mosaic gene deletion, gene regulatory network analysis

    PMID:33712605

    Open questions at the time
    • Direct regulatory relationships to YAP1/SF3B2 not biochemically established
    • Single lab
  30. 2023 Medium

    Showed PGC-1α with ERRα coordinates mitochondrial translation and supercomplex assembly, an axis impaired in sarcopenic muscle and restored by exercise.

    Evidence Mouse aging and exercise models, PGC-1α TG/KO, mitochondrial translation assays, ERRα interaction

    PMID:37639610

    Open questions at the time
    • Mechanism coupling nuclear coactivation to mitochondrial translation not resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct PGC-1α post-translational marks and isoforms are decoded into program-specific transcription factor recruitment — selecting gluconeogenic, mitochondrial, thermogenic, autophagic, or angiogenic outputs in a given cell — remains unresolved.
  • No unified model linking specific acetyl/phospho marks to specific transcription-factor partner engagement
  • Genome-wide direct binding maps across tissues incomplete
  • Structural basis of coactivator–receptor selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9612973 Autophagy 3
Partners
ERRAERRGEWSFBXW7HES1IRF4SIRT1TP53

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PGC-1α stimulates mitochondrial biogenesis and respiration in muscle cells by inducing NRF-1 and NRF-2 gene expression, and by directly binding to and coactivating NRF-1 on the promoter of mitochondrial transcription factor A (mtTFA), a direct regulator of mitochondrial DNA replication/transcription. PGC-1α also induces UCP-2 expression. Overexpression in muscle cells, reporter/promoter assays, direct binding/coactivation experiments, mitochondrial function assays Cell High 10412986
1999 Human PPARGC1A encodes a 91-kDa protein with 94% amino acid identity to the mouse ortholog, spans ~67 kb with 13 exons, maps to chromosome 4p15.1, and is expressed in heart, skeletal muscle, kidney, liver, brain, pancreas, and perirenal adipose tissue. cDNA cloning, genomic organization analysis, Northern blotting, chromosomal mapping Genomics High 10585775
2005 SIRT1 interacts with PGC-1α and deacetylates it at specific lysine residues in an NAD+-dependent manner. SIRT1-mediated deacetylation of PGC-1α induces gluconeogenic genes and hepatic glucose output, but does not regulate PGC-1α effects on mitochondrial genes. Pyruvate-induced fasting signals upregulate SIRT1 protein in liver, which then modulates PGC-1α activity. Co-immunoprecipitation, in vitro deacetylation assays, adenoviral gain/loss-of-function, hepatic glucose output measurement, gene expression analysis Nature High 15744310
2003 PGC-1α directly activates CYP7A1 (cholesterol 7α-hydroxylase) gene transcription in hepatic cells, increasing bile acid biosynthesis. PGC-1α activates the CYP7A1 promoter in transient transfection assays, and is co-induced with CYP7A1 in livers of fasted and streptozotocin-diabetic mice. Adenoviral overexpression in HepG2 cells, transient transfection/promoter assays, bile acid biosynthesis measurement, in vivo mouse models The Journal of biological chemistry High 14522988
2010 PGC-1α promotes peroxisomal remodeling and biogenesis in brown adipose tissue in response to thermogenic stimuli. Ectopic PGC-1α expression recapitulates peroxisomal expansion in vitro and in vivo, and β-adrenergic stimulation of PGC-1α−/− cells shows blunted induction of peroxisomal gene expression. This occurs through a PPARα-independent mechanism. PGC-1α overexpression, PGC-1α knockout cells, β-adrenergic stimulation, peroxisomal gene expression analysis, organelle imaging Proceedings of the National Academy of Sciences of the United States of America High 21059926
2012 PGC-1α expression in muscle stimulates increased expression of FNDC5, a membrane protein cleaved and secreted as irisin. Irisin acts on white adipose cells to stimulate UCP1 expression and a brown-fat-like thermogenic program. Irisin is induced with exercise in mice and humans and increases energy expenditure. Transgenic mouse overexpression, cell culture experiments, in vivo irisin treatment, gene expression analysis, metabolic measurement Nature High 22237023
2013 In the hippocampus, neuronal FNDC5 gene expression is regulated by PGC-1α; Pgc1a−/− mice show reduced Fndc5 expression in the brain. Forced FNDC5 expression in cortical neurons increases Bdnf expression, and peripheral delivery of FNDC5 via adenoviral vectors elevates blood irisin and induces BDNF expression in the hippocampus. Pgc1a knockout mice, primary neuron cultures, adenoviral overexpression, RNAi knockdown, gene expression analysis Cell metabolism High 24120943
2014 IRF4 is a transcriptional partner of PGC-1α in adipocytes. IRF4 interacts with PGC-1α and together they drive UCP1 expression. Cold, β-agonists, or forced PGC-1α expression are unable to induce thermogenic gene expression in the absence of IRF4. IRF4 also induces PGC-1α and PRDM16 expression. Co-immunoprecipitation, IRF4 knockout (UCP1+ cell-specific), IRF4 overexpression, gene expression, energy expenditure measurement, cold tolerance assay Cell High 24995979
2009 SIRT1 and AMPK directly affect PGC-1α activity through deacetylation and phosphorylation, respectively, acting as an energy-sensing network to control cellular energy expenditure. Transgenic mouse models, phosphorylation and deacetylation assays, metabolic measurements (review synthesizing experimental findings) Current opinion in lipidology Medium 19276888
2009 PGC-1α and PGC-1β control mitochondrial density in neurons (cortical, midbrain, and cerebellar granule) in an additive and independent manner. Overexpression of SIRT1 deacetylase or suppression of GCN5 acetyltransferase activates PGC-1α transcriptional activity and increases mitochondrial density specifically through PGC-1α (not PGC-1β), as SIRT1 overexpression was ineffective when PGC-1α was suppressed by shRNA. Neuronal overexpression and shRNA knockdown, SIRT1 overexpression, GCN5 suppression, mitochondrial density measurement The Journal of biological chemistry Medium 19542216
2001 PGC-1α interacts with components of the splicing machinery, suggesting a role in coordinating transcription and RNA splicing. PGC-1α also regulates multiple nuclear receptors beyond PPARγ and acts as a versatile coactivator. Protein interaction studies, biochemical assays (review synthesizing experimental findings) Trends in endocrinology and metabolism: TEM Low 11551810
2002 PGC-1α (and PGC-1β) directly interact with ERRγ (estrogen receptor-related receptor gamma) and potently augment its transcriptional activation. The constitutive AF-2 domain of ERRγ is required for this synergistic enhancement, and an additional amino-terminal activation function specific to ERRγ2 isoform was identified for PGC-1α. In vitro direct interaction assays, mammalian cell transfection, receptor truncation analysis, reporter assays Biochemical and biophysical research communications Medium 12470660
2011 ATGL-mediated lipolysis generates lipid ligands for PPAR activation. ATGL deficiency in mice decreases PGC-1α and PGC-1β expression in heart, leading to severely disrupted mitochondrial substrate oxidation and lethal cardiomyopathy. Pharmacological PPAR-α agonist treatment of ATGL-deficient mice completely reverses mitochondrial defects, restores heart function, and prevents death. ATGL knockout mice, PPAR-α agonist treatment, mitochondrial function assays, gene expression analysis, cardiac function measurement Nature medicine High 21857651
2012 PGC-1α controls extrasynaptic NMDAR (NMDАР_EX) activity in neurons. Knockdown of endogenous PGC-1α increased NMDAR_EX activity and vulnerability to excitotoxic insults in rat cortical neurons. Exogenous PGC-1α expression reduced NMDAR_EX currents without affecting synaptic NMDAR activity. Mutant Huntingtin (mHtt)-mediated suppression of PGC-1α expression and increased NMDAR_EX activity were nonadditive, consistent with a common mechanism. RNAi knockdown, overexpression in primary neurons, electrophysiology (NMDAR current measurement), excitotoxicity assays, epistasis experiments with mHtt The Journal of neuroscience : the official journal of the Society for Neuroscience High 22593067
2012 PGC-1α regulates VEGFA expression in retinal cells and is required for normal retinal vessel development and for pathological neovascularization. PGC-1α−/− mice show reduced early retinal vascular outgrowth and reduced capillary density. In oxygen-induced retinopathy, PGC-1α is induced in the inner nuclear layer and PGC-1α−/− mice are protected against pathological neovascularization, with decreased VEGFA expression. PGC-1α knockout mice, oxygen-induced retinopathy model, VEGFA expression analysis, retinal vascular morphometry The American journal of pathology High 23141926
2015 EWS (Ewing sarcoma protein) stabilizes PGC-1α protein by preventing its ubiquitination and proteasomal degradation. Loss of EWS leads to increased expression of E3 ubiquitin ligase FBXW7 and rapid degradation of PGC-1α. Depletion of FBXW7 in EWS-null cells restores PGC-1α expression and mitochondrial density. EWS knockout cells and mice, ubiquitination assays, proteasome inhibitor experiments, FBXW7 knockdown, mitochondrial density measurement Proceedings of the National Academy of Sciences of the United States of America High 25918410
2016 Endothelial PGC-1α promotes eNOS expression and activity to protect against vascular dysfunction. Endothelial-specific PGC-1α knockout mice are sensitized to endothelial dysfunction and hypertension in response to angiotensin II, while transgenic overexpression is protective. The orphan nuclear receptor ERRα is required to coordinate PGC-1α-induced eNOS expression. Endothelial-specific KO and TG mice, angiotensin II treatment, eNOS inhibitor experiments, eNOS KO mice, vascular function assays Scientific reports High 27910955
2017 The Notch target gene Hes1 directly binds to the regulatory region of PGC-1α (shown by ChIP), suppressing its expression and causing fatty acid oxidation defects and kidney fibrosis. PGC-1α overexpression in tubular cells restores mitochondrial content and reverses the fatty acid oxidation defect induced by Notch overexpression. Chromatin immunoprecipitation (ChIP), transgenic mouse overexpression, Notch1 transgenic mice, gene expression analysis, mitochondrial content measurement Journal of the American Society of Nephrology : JASN High 28751525
2017 A fraction of cellular PGC-1α localizes to the nucleolus and associates with ribosomal DNA upon activation, boosting recruitment of RNA polymerase I and UBF to the rDNA promoter and inducing RNA polymerase I transcription. This links ribosomal biogenesis to mitochondrial biogenesis. PGC-1α subcellular fractionation/localization, ChIP on rDNA promoter (RNA Pol I, UBF), cell culture and mouse models, analysis in human subjects and Huntington's disease samples Scientific reports Medium 28819135
2018 PGC-1α interacts with ERRα and recruits it to the ERRα response element in the proximal MPC1 (mitochondrial pyruvate carrier 1) promoter, activating MPC1 transcription. MPC1 is required for PGC-1α-induced pyruvate-dependent mitochondrial oxygen consumption, as the MPC inhibitor UK5099 blocks this effect. PGC-1α overexpression and siRNA knockdown, reporter assays with ERRα response element, Co-IP, mitochondrial oxygen consumption with pharmacological MPC inhibitor The Biochemical journal Medium 29669911
2018 Mutant p53 binds and regulates PGC-1α to enhance tumor cell migration and metastasis. This regulation is markedly impacted by the codon 72 polymorphism (Pro72Arg): tumor cells with the R72 variant of mutant p53 show increased PGC-1α function, greatly increased mitochondrial function, and increased metastatic capability. Co-immunoprecipitation (mutant p53–PGC-1α), migration/metastasis assays, mitochondrial function assays, in vivo models Genes & development Medium 29463573
2019 PGC-1α determines the relative ratio of IRS1 and IRS2 in hepatocytes: it drives IRS2 expression downstream of glucagon/cAMP/CREB signaling while simultaneously reducing IRS1 expression, thereby modulating insulin receptor signaling via AKT. This IRS2 induction is CREB-dependent and is essential for insulin-mediated suppression of gluconeogenesis. Gain- and loss-of-function in primary mouse hepatocytes, gene/protein expression, ex vivo glucose production, in vivo overexpression Proceedings of the National Academy of Sciences of the United States of America Medium 30770439
2019 PGC-1α upregulates autophagy in vascular smooth muscle cells via SQSTM1/p62, reducing cellular senescence. SQSTM1 is identified as a direct target of PPARGC1A. ppargc1a-deficient VSMCs show reduced autophagosome number, reduced SQSTM1 expression, and increased senescence; these effects are phenocopied by SQSTM1 deficiency. ppargc1a knockout VSMCs, adenoviral PPARGC1A overexpression, autophagy inhibitors, siRNA (SQSTM1, ATG5), electron microscopy, SA-β-gal senescence assay Autophagy Medium 31441382
2019 PGC-1α promotes autophagy in fibroblasts to drive TGFβ-induced myofibroblast differentiation and collagen release. Fibroblast-specific PGC-1α knockout in mice prevents bleomycin- and constitutively active TGFβR1-induced skin fibrosis. Pharmacological inhibition of PGC-1α by SR18292 induces regression of pre-established fibrosis. Fibroblast-specific KO mice, PGC-1α knockdown in human fibroblasts, two mouse fibrosis models, SR18292 pharmacological inhibition, autophagy reporter studies Annals of the rheumatic diseases High 32482644
2020 PGC-1α isoform 4 (PGC-1α4) uniquely enhances expression of anti-apoptotic gene programs and attenuates hepatocyte apoptosis in response to TNFα or LPS. In contrast, canonical PGC-1α1 decreases inflammatory gene networks but does not prevent hepatocyte death. The isoforms have distinct yet complementary roles. Primary mouse hepatocyte gain- and loss-of-function, microarray analysis, apoptosis measurement, TNFα/LPS treatment, in vivo models Molecular metabolism Medium 32180561
2021 Microglial PGC-1α promotes autophagy and mitophagy through ULK1 (as revealed by ChIP-Seq showing PGC-1α binding sites, including at ULK1 targets) and interacts with ERRα to induce ULK1 expression. This reduces NLRP3 activation and neuroinflammation after ischemic stroke. Pharmacological inhibition or knockdown of ULK1 abolishes the neuroprotective effects of PGC-1α. Microglia-specific PGC-1α transgenic mice, MCAO model, ChIP-Seq, ULK1 pharmacological inhibition and siRNA knockdown, NLRP3/cytokine measurement, autophagy/mitophagy assays Genome medicine Medium 33771213
2021 PGC-1/PPAR signaling active in vivo but not in pluripotent stem cell-derived cardiomyocytes mediates cardiomyocyte maturation. Mosaic gene deletion reveals this signaling regulates maturation through YAP1 and SF3B2 as previously unrecognized downstream proteins. Single-cell transcriptomics, mosaic gene deletion, gene regulatory network analysis, single cardiomyocyte isolation from neonatal to adult hearts Nature communications Medium 33712605
2018 PGC-1α, together with nuclear receptor ERRα, dose-dependently enhances ALT2 (alanine aminotransferase 2) promoter activity in skeletal muscle cells, increasing alanine production. PGC-1α knockdown reduces ALT2 gene expression, and PGC-1α/ERRα complex regulates alanine metabolism during fasting. PGC-1α overexpression and knockdown in C2C12 myoblasts, reporter assay of ALT2 promoter, alanine measurement in cells and medium PloS one Medium 29315328
2019 The PGC-1α/PPARβ axis is a crucial mediator of Ucp3 (uncoupling protein 3) expression in skeletal muscle cells via transactivation of a distal PPAR response element in the Ucp3 promoter, as revealed by quantitative ChIP. Ucp3 is shown to be essential for PGC-1α-induced oxidative capacity. ChIP on Ucp3 promoter PPAR response element, PGC-1α overexpression, siRNA/knockdown of PPARβ and UCP3, oxidative capacity measurement The Journal of physiology Medium 31228206
2018 PGC-1α and PGC-1β increase protein synthesis in C2C12 myotubes via ERRα, independently of Akt/mTOR signaling. Suppression of ERRα attenuates PGC-1α/β-induced protein synthesis and myotube diameter increases, while PI3K and mTOR inhibitors do not block this effect. PGC-1α/β overexpression in C2C12, PI3K/mTOR inhibitors, ERRα siRNA knockdown, protein synthesis measurement, myotube diameter measurement Frontiers in physiology Medium 30356878
2020 In zebrafish, ppargc1a is essential for ciliogenesis in nodal, mono-, and multiciliated cells and for renal tubule ciliated cell fate specification during embryogenesis. This function depends on prostaglandin signaling: ppargc1a-deficient animals show reduced ptgs1 (prostaglandin-endoperoxide synthase 1) expression, and ciliogenesis and renal MCC fate are rescued by PGE2 treatment or ptgs1 overexpression. Zebrafish ppargc1a knockdown/knockout, PGE2 rescue, ptgs1 knockdown and overexpression, cilia imaging, renal MCC fate analysis Cell reports Medium 33176142
2023 PGC-1α, together with ERRα, regulates mitochondrial translation in skeletal muscle. An age-related impairment in mitochondrial translation is observed in sarcopenic muscle, and exercise (a potent PGC-1α inducer) rectifies this impairment. PGC-1α with ERRα coordinates expression of nuclear- and mitochondrial-encoded proteins for supercomplex formation. Mouse skeletal muscle aging model, exercise intervention, PGC-1α transgenic/knockout models, mitochondrial translation assays, ERRα interaction studies Proceedings of the National Academy of Sciences of the United States of America Medium 37639610
2006 FOXO1 is neither required nor sufficient for PGC-1α stimulation of G6Pase-luciferase fusion gene expression in cells, indicating that the transcriptional interaction between FOXO1 and PGC-1α in gluconeogenesis is indirect (NEGATIVE finding contradicting the proposal that PGC-1α acts directly through FOXO1). Transfection reporter assays in cells, G6Pase-luciferase reporter, FOXO1 gain/loss-of-function Nature Medium 17024043

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 3781 22237023
1999 Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 3411 10412986
2005 Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2642 15744310
2009 PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current opinion in lipidology 1343 19276888
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