PPARGC1A

Summary

PPARGC1A (PPARG coactivator 1 alpha, HGNC:9237) is a protein-coding gene on chromosome 4p15.2, encoding Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Q9UBK2). Transcriptional coactivator for steroid receptors and nuclear receptors.

The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with PPARgamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

Source: NCBI Gene 10891 — RefSeq curated summary.

At a glance

• GWAS associations: 34
• Clinical variants (ClinVar): 151 total
• Phenotypes (HPO): 47
• Druggable target: yes
• Transcription factor: yes — 34 downstream targets (CollecTRI)
• MANE Select transcript: NM_013261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9237
Approved symbol	PPARGC1A
Name	PPARG coactivator 1 alpha
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	PGC1, PGC1A, PGC-1alpha, PPARAGCIα
Ensembl gene	ENSG00000109819
Ensembl biotype	protein_coding
OMIM	604517
Entrez	10891

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding_CDS_not_defined, 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000264867, ENST00000503714, ENST00000505469, ENST00000506055, ENST00000507342, ENST00000507380, ENST00000508380, ENST00000509642, ENST00000509702, ENST00000512169, ENST00000513205, ENST00000514479, ENST00000514494, ENST00000514517, ENST00000515534, ENST00000613098, ENST00000907769, ENST00000907770, ENST00000907771

RefSeq mRNA: 8 — MANE Select: NM_013261 NM_001330751, NM_001330752, NM_001330753, NM_001354825, NM_001354826, NM_001354827, NM_001354828, NM_013261

CCDS: CCDS3429, CCDS87211, CCDS87212

Canonical transcript exons

ENST00000264867 — 13 exons

Exon	Start	End
ENSE00001490990	23792021	23795925
ENSE00003472126	23813021	23813125
ENSE00003479263	23829463	23829585
ENSE00003500076	23828400	23828604
ENSE00003500342	23824463	23824508
ENSE00003546216	23801730	23801881
ENSE00003586701	23831557	23831751
ENSE00003595936	23813690	23814605
ENSE00003602066	23824280	23824353
ENSE00003621411	23812747	23812867
ENSE00003638685	23884752	23884931
ENSE00003689219	23802224	23802345
ENSE00003849976	23889904	23890047

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 96.88.

FANTOM5 (CAGE): breadth broad, TPM avg 8.6869 / max 577.6777, expressed in 791 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51638	4.1918	547
51666	0.9418	329
51664	0.9249	219
51665	0.6527	251
51639	0.5939	243
51642	0.5824	71
51663	0.3623	117
51624	0.1321	38
51626	0.0736	11
51640	0.0568	17

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	96.88	gold quality
body of tongue	UBERON:0011876	93.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.91	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.87	gold quality
vastus lateralis	UBERON:0001379	91.83	gold quality
right atrium auricular region	UBERON:0006631	91.82	gold quality
cardiac atrium	UBERON:0002081	91.48	gold quality
parotid gland	UBERON:0001831	91.03	gold quality
biceps brachii	UBERON:0001507	90.92	gold quality
quadriceps femoris	UBERON:0001377	90.70	gold quality
skeletal muscle tissue	UBERON:0001134	90.59	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.32	gold quality
nephron tubule	UBERON:0001231	90.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.01	gold quality
muscle organ	UBERON:0001630	88.98	gold quality
cardiac ventricle	UBERON:0002082	88.97	gold quality
skeletal muscle organ	UBERON:0014892	88.97	gold quality
heart left ventricle	UBERON:0002084	88.94	gold quality
liver	UBERON:0002107	88.89	gold quality
kidney	UBERON:0002113	88.72	gold quality
diaphragm	UBERON:0001103	88.70	silver quality
gastrocnemius	UBERON:0001388	88.69	gold quality
muscle of leg	UBERON:0001383	88.32	gold quality
choroid plexus epithelium	UBERON:0003911	88.32	gold quality
adult mammalian kidney	UBERON:0000082	88.24	gold quality
middle temporal gyrus	UBERON:0002771	88.17	gold quality
left ventricle myocardium	UBERON:0006566	88.11	gold quality
medial globus pallidus	UBERON:0002477	88.00	gold quality
muscle tissue	UBERON:0002385	87.97	gold quality
right lobe of liver	UBERON:0001114	87.91	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	468.39
E-CURD-119	yes	44.65
E-ANND-3	yes	5.97
E-GEOD-81383	no	471.65
E-ENAD-17	no	410.92

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

34 targets.

Target	Regulation
ALDOB	Activation
APLN
APOA5	Activation
APOC3	Activation
BMAL1	Activation
CAV3	Activation
CDKN1A
COX4I1	Activation
COX5B	Activation
CPT1B	Activation
CYCS	Activation
CYP2C9	Unknown
CYP7A1	Activation
FGF21
FOXO3	Repression
HMOX1
IDE	Activation
IGF1	Activation
LDLR	Repression
MFN2	Activation
MLYCD	Unknown
MSTN	Repression
NFKB1	Repression
NPC1L1
NR1D1	Activation
NRF1	Activation
OTC	Activation
PCK2	Activation
PPARGC1A	Activation
SLC2A4	Activation

Upstream regulators (CollecTRI, top): ATF2, ATF4, ATF5, ATF6, BHLHE40, BMP7, CEBPB, CEBPG, CREB1, CRTC1, DDIT3, DNMT1, E2F4, ESR1, ESRRA, ESRRG, FLCN, FOXA3, FOXC1, FOXL2, FOXO1, FOXO3, FOXO4, FOXO6, GATA4, HNF4A, IRF7, JUN, KAT2A, KLF15, MEF2A, MEF2C, MEF2D, MITF, MYOD1, NCOA1, NCOR2, NFATC1, NFKB, NR0B1

miRNA regulators (miRDB)

319 targeting PPARGC1A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 40)

• PRC is a functional relative of PGC-1 that operates through NRF-1 and possibly other activators in response to proliferative signals (PMID:11340167)
• Mutation analysis. A widespread Gly482Ser polymorphism of PGC-1 is associated with a 1.34 genotype relative risk of Type II diabetes mellitus (PMID:11793024)
• Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity. (PMID:11875072)
• Egr-1 is necessary and sufficient to activate human PPARgamma1 gene expression in VSMC (PMID:12011097)
• no association with type II diabetes and G482S polymorphism was detected in moderate and morbidly obese subjects (PMID:12032643)
• results of this study suggested that the PGC-1 gene might be implicated in the pathogenesis of Type II diabetes (PMID:12107756)
• identification of a specific molecular repressor of the gene (PMID:12397057)
• PGC-1 alpha serves as a co-activator for the liver X receptor (LXR) alpha, known to contribute to the regulation of cellular cholesterol homoeostasis (PMID:12470296)
• role of LXXLL domain for ligand-dependent and ligand-independent interaction and coactivation of peroxisome proliferator-activated receptor gamma (PMID:12502716)
• PGC-1 can induce the fatty acid oxidation enzyme MCAD (medium-chain acyl-coenzyme A dehydrogenase) in an ERRalpha-dependent manner (PMID:12522104)
• Exercise induces dramatic transient increase in PGC-1alpha transcription and mRNA content in human skeletal muscle. PGC-1alpha may coordinate activation of metabolic genes in human muscle in response to exercise. (PMID:12563009)
• Data describe the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1, PPAR gamma, insulin receptor substrate-1, glucose transporter isoform-4, and mitochondrial uncoupling protein-1 in adipose tissue. (PMID:12565902)
• PPARGC1 can participate in blood pressure control, and sequence substitutions at its gene locus confer an increased risk of hypertension to a substantial proportion of men. (PMID:12574109)
• results indicate that signaling via protein kinase B to forkhead transcription factor FKHR can account for the effect of insulin to regulate peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity via the insulin response sequence (PMID:12606503)
• data indicate that the Gly482Ser missense polymorphism in PGC-1 has metabolic consequences on lipid metabolism that could influence insulin secretion (PMID:12606537)
• Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM. (PMID:12832613)
• Down-regulation of peroxisome-proliferator activated receptor-gamma coactivator 1 is associated with local recurrence and metastasis in breast cancer (PMID:12866036)
• in human skeletal muscle, PGC-1alpha mRNA increased more after exercise with restricted blood flow than in the nonrestricted condition. (PMID:12972445)
• PGC-1alpha has a fundamental role in activating CYP7A1 and bile acid biosynthesis (PMID:14522988)
• Polymorphism associated with insulin resistance affects insulin snssitivity by interacting with PC-1 polymorphism (PMID:14574455)
• Increases in PGC-1 and PPAR-alpha levels may play an important role in changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin induced by endurance training. (PMID:14633846)
• Examines whether common polymorphism (Gly482Ser) within the gene modifies the association between physical activity energy expenditure and VO2max (PMID:14652494)
• our data suggest that the transcriptional activity of PPARgamma may not only be decreased by mutation but also by downregulation of the coactivator PGC-1 of PPARgamma. (PMID:14670614)
• an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate ERRalpha expression level; regulatory polymorphism studied may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues (PMID:14978033)
• Borderline significant differences of four-loci haplotype distributions in downstream haplotype block. Haplotype associated with strongest insulin response to glucose conferred lowest risk of type 2 diabetes. (PMID:15111510)
• Gly482Ser variant in PGC-1 is not associated with diabetes-related traits or skeletal muscle fiber type composition. (PMID:15146371)
• both PPARgamma and its coactivator PGC-1 play important roles in the development and progression of breast cancer (PMID:15254719)
• ligand-activated PXR interferes with HNF-4 signaling by targeting the common coactivator PGC-1, which underlies physiologically relevant inhibitory cross-talk between drug metabolism and cholesterol/glucose metabolism (PMID:15322103)
• PGC-1alpha functions as a potent coactivator for FXR and further implicates its role in the regulation of genes that are involved in bile acid and lipid metabolism. (PMID:15329387)
• study of the crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha (PMID:15337744)
• Gly482Ser polymorphism of the PGC-1 gene should be considered as a risk factor for the development of type 2 diabetes in Caucasians. (PMID:15581067)
• 482Ser allele of the PGC-1alpha gene is associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. (PMID:15592662)
• sex-specific association between Gly482Ser polymorphism and arterial hypertension in type 2 diabetic men. (PMID:15599700)
• summary, our data indicate a role for the Gly482Ser genotype in determining aerobic fitness. (PMID:15705733)
• Ser allele of PGC-1alpha Gly482Ser confers a significantly reduced risk of hypertension in whites. (PMID:15738346)
• Data demonstrate that the multi-hormone response element of the estrogen-related receptor-alpha (ERRalpha) gene is a target for ERRgamma transactivation, which is enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. (PMID:15821111)
• two variations in the PGC-1alpha gene might not contribute to the risk of hypertension and type 2 diabetes in the Chinese population studied here (PMID:15824463)
• Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased PGC1 mRNA expression following treatment with various antidiabetic agents. (PMID:15864539)
• PGC-1 alpha serves as a coactivator for the vitamin D receptor. (PMID:15908514)
• PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes. (PMID:15912394)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppargc1a	ENSDARG00000067829
mus_musculus	Ppargc1a	ENSMUSG00000029167
rattus_norvegicus	Ppargc1a	ENSRNOG00000004473
drosophila_melanogaster	srl	FBGN0037248

Paralogs (2): PPRC1 (ENSG00000148840), PPARGC1B (ENSG00000155846)

Protein

Protein identifiers

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha — Q9UBK2 (reviewed: Q9UBK2)

Alternative names: Ligand effect modulator 6

All UniProt accessions (2): Q9UBK2, D6RBF3

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism. Acts as a key regulator of gluconeogenesis: stimulates hepatic gluconeogenesis by increasing the expression of gluconeogenic enzymes, and acting together with FOXO1 to promote the fasting gluconeogenic program. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. Required for oscillatory expression of clock genes, such as BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK.

Subunit / interactions. Homooligomer. Interacts with MYBBP1A; inhibits MYBBP1A transcriptional activation. Interacts with PRDM16, LPIN1 and PML. Interacts (via LXXLL motif) with RORA and RORC (via AF-2 motif); activates RORA and RORC transcriptional activation. Interacts with LRPPRC. Interacts with FOXO1. Interacts with NR5A2.

Subcellular location. Nucleus. PML body Nucleus Cytoplasm. Nucleus Nucleus. PML body Nucleus.

Tissue specificity. Heart, skeletal muscle, liver and kidney. Expressed at lower levels in brain and pancreas and at very low levels in the intestine and white adipose tissue. In skeletal muscle, levels were lower in obese than in lean subjects and fasting induced a 2-fold increase in levels in the skeletal muscle in obese subjects.

Post-translational modifications. Phosphorylation by AMPK in skeletal muscle increases activation of its own promoter. Phosphorylated by CLK2. Heavily acetylated by KAT2A/GCN5 under conditions of high nutrients, leading to inactivation of PPARGC1A. Deacetylated by SIRT1 in low nutrients/high NAD conditions, leading to its activation. Ubiquitinated. Ubiquitination by RNF34 induces proteasomal degradation.

Induction. Transcription is repressed by ZNF746 which binds to ‘insulin response sequences’ its promoter.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative promoter usage. May be involved in gluconeogenesis, liver-specific.

Isoforms (10)

UniProt ID	Names	Canonical?
Q9UBK2-1	1	yes
Q9UBK2-2	NT-7a
Q9UBK2-3	B5
Q9UBK2-4	B4
Q9UBK2-5	B4-8a
Q9UBK2-6	B5-NT
Q9UBK2-7	B4-3ext
Q9UBK2-8	8a
Q9UBK2-9	9, L-PGG-1alpha
Q9UBK2-10	10

RefSeq proteins (8): NP_001317680, NP_001317681, NP_001317682, NP_001341754, NP_001341755, NP_001341756, NP_001341757, NP_037393* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034605	PGC-1	Family
IPR034833	PPARGC1A_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (47 total): modified residue 15, splice variant 11, region of interest 8, compositionally biased region 6, sequence variant 2, helix 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

47 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9F7W	X-RAY DIFFRACTION	1.25
8BF1	X-RAY DIFFRACTION	1.36
6MS7	X-RAY DIFFRACTION	1.43
6W9L	X-RAY DIFFRACTION	1.45
9IWO	X-RAY DIFFRACTION	1.49
3U9Q	X-RAY DIFFRACTION	1.52
8YT9	X-RAY DIFFRACTION	1.59
9IWN	X-RAY DIFFRACTION	1.59
6NWL	X-RAY DIFFRACTION	1.59
3B1M	X-RAY DIFFRACTION	1.6
3V9V	X-RAY DIFFRACTION	1.6
6W9K	X-RAY DIFFRACTION	1.6
9F7X	X-RAY DIFFRACTION	1.63
3V9T	X-RAY DIFFRACTION	1.65
6NWK	X-RAY DIFFRACTION	1.65
5Q0I	X-RAY DIFFRACTION	1.7
9T5S	X-RAY DIFFRACTION	1.74
6IZN	X-RAY DIFFRACTION	1.75
8YWU	X-RAY DIFFRACTION	1.77
5Z5S	X-RAY DIFFRACTION	1.8
5Z6S	X-RAY DIFFRACTION	1.8
6IZM	X-RAY DIFFRACTION	1.8
6K0T	X-RAY DIFFRACTION	1.84
8YT6	X-RAY DIFFRACTION	1.85
5TWO	X-RAY DIFFRACTION	1.93
6FZF	X-RAY DIFFRACTION	1.95
6KXX	X-RAY DIFFRACTION	1.95
8YU8	X-RAY DIFFRACTION	1.95
5UNJ	X-RAY DIFFRACTION	1.96
6KXY	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBK2-F1	53.47	0.09

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (15): 79, 146, 178, 184, 254, 271, 278, 321, 347, 413, 442, 451, 539, 758, 779

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-2151209	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9707616	Heme signaling
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-9854907	Regulation of MITF-M dependent genes involved in metabolism
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression

MSigDB gene sets: 554 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_CIRCADIAN_RHYTHM, ATF_B, REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_LIPID_MODIFICATION, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, AAGCAAT_MIR137, MULLIGHAN_NPM1_SIGNATURE_3_UP, TAATAAT_MIR126, WALLACE_PROSTATE_CANCER_RACE_UP, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_RESPONSE_TO_DIETARY_EXCESS

GO Biological Process (35): temperature homeostasis (GO:0001659), intracellular glucose homeostasis (GO:0001678), response to dietary excess (GO:0002021), gluconeogenesis (GO:0006094), regulation of DNA-templated transcription (GO:0006355), transcription initiation at RNA polymerase II promoter (GO:0006367), mRNA processing (GO:0006397), mitochondrion organization (GO:0007005), digestion (GO:0007586), RNA splicing (GO:0008380), positive regulation of gene expression (GO:0010628), response to muscle activity (GO:0014850), fatty acid oxidation (GO:0019395), respiratory electron transport chain (GO:0022904), circadian regulation of gene expression (GO:0032922), cellular response to oxidative stress (GO:0034599), response to starvation (GO:0042594), regulation of circadian rhythm (GO:0042752), negative regulation of neuron apoptotic process (GO:0043524), cellular respiration (GO:0045333), positive regulation of gluconeogenesis (GO:0045722), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of fatty acid oxidation (GO:0046321), negative regulation of smooth muscle cell proliferation (GO:0048662), protein stabilization (GO:0050821), brown fat cell differentiation (GO:0050873), neuron apoptotic process (GO:0051402), adipose tissue development (GO:0060612), protein-containing complex assembly (GO:0065003), energy homeostasis (GO:0097009), positive regulation of cold-induced thermogenesis (GO:0120162), developmental process (GO:0032502), homeostatic process (GO:0042592), rhythmic process (GO:0048511)

GO Molecular Function (14): DNA binding (GO:0003677), transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), nuclear receptor binding (GO:0016922), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), sequence-specific DNA binding (GO:0043565), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), lncRNA binding (GO:0106222), DNA-binding transcription factor binding (GO:0140297), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transcription factor binding (GO:0008134)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), PML body (GO:0016605), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Mitochondrial biogenesis	2
Circadian clock	2
Regulation of lipid metabolism by PPARalpha	1
Adipogenesis	1
SUMO E3 ligases SUMOylate target proteins	1
Transcriptional regulation by RUNX2	1
FOXO-mediated transcription	1
Cellular responses to stress	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Transcriptional regulation of brown and beige adipocyte differentiation	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of gene expression	3
response to nutrient levels	2
RNA processing	2
circadian rhythm	2
nucleic acid binding	2
DNA binding	2
binding	2
multicellular organismal-level homeostasis	1
glucose homeostasis	1
intracellular chemical homeostasis	1
energy homeostasis	1
glucose metabolic process	1
hexose biosynthetic process	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
DNA-templated transcription initiation	1
transcription by RNA polymerase II	1
mRNA metabolic process	1
organelle organization	1
multicellular organismal process	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
response to activity	1
fatty acid metabolic process	1
lipid oxidation	1
electron transport chain	1
cellular respiration	1
response to oxidative stress	1
cellular response to chemical stress	1
response to stress	1
regulation of biological process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
energy derivation by oxidation of organic compounds	1
transcription regulator activity	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
RNA polymerase II-specific DNA-binding transcription factor binding	1

Protein interactions and networks

STRING

5655 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPARGC1A	PPARG	P37231	999
PPARGC1A	PPARA	Q07869	999
PPARGC1A	SIRT1	Q96EB6	998
PPARGC1A	ESRRA	P11474	998
PPARGC1A	NRF1	Q16656	998
PPARGC1A	FOXO1	Q12778	997
PPARGC1A	YY1	P25490	995
PPARGC1A	PRDM16	Q9HAZ2	995
PPARGC1A	HNF4A	P41235	993
PPARGC1A	FOXO3	O43524	979
PPARGC1A	CREB1	P16220	963
PPARGC1A	LPIN1	Q14693	947
PPARGC1A	UCP1	P25874	943
PPARGC1A	NFE2L2	Q16236	940
PPARGC1A	NCOA1	Q15788	936

IntAct

67 interactions, top by confidence:

A	B	Type	Score
ESRRA	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.890
ESRRA	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.890
PPARGC1A	ESRRA	psi-mi:“MI:0915”(physical association)	0.890
ESRRG	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.720
ESRRG	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.720
PPARGC1A	ESRRG	psi-mi:“MI:0407”(direct interaction)	0.720
HNF4A	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.650
PPARG	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.590
PPARGC1A	PPARG	psi-mi:“MI:0407”(direct interaction)	0.590
ESRRG	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.560
RARB	PPARGC1A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (167): PPARGC1A (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), PPARGC1A (Biochemical Activity), PPARG (Affinity Capture-Western), PPARGC1A (Biochemical Activity), NRIP1 (Affinity Capture-Western), PPARGC1A (Reconstituted Complex), PPARGC1A (Reconstituted Complex), PPARG (Two-hybrid), PPARG (Reconstituted Complex), PPARGC1A (Two-hybrid), PPARGC1A (Two-hybrid), NFKB1 (Affinity Capture-Western), RELA (Affinity Capture-Western), PPARG (Affinity Capture-Western)

ESM2 similar proteins: A0A140LFM6, A2CEZ5, A2RV70, A2VCZ5, A5WUN7, A6H5Y1, A8MW92, B0S6S9, D3ZJ47, E7FAP1, O43823, O70343, P62932, Q16533, Q2T9I9, Q499E5, Q4R815, Q5CZC0, Q5REF4, Q5SW75, Q5SWW4, Q5T5Y3, Q63014, Q65Z40, Q66H35, Q6IRN6, Q6JPI3, Q6KAQ7, Q6PCB5, Q71F56, Q76I76, Q76I79, Q865B6, Q865B7, Q8CB14, Q8CDG5, Q8IUR6, Q8IX21, Q8JZS6, Q8K3V7

Diamond homologs: O70343, Q5VV67, Q6NZN1, Q811R2, Q865B6, Q865B7, Q86YN6, Q8VHJ7, Q9QYK2, Q9UBK2

SIGNOR signaling

71 interactions.

A	Effect	B	Mechanism
MAPK14	up-regulates	PPARGC1A	phosphorylation
FOXO1	down-regulates	PPARGC1A
AKT	“down-regulates activity”	PPARGC1A	phosphorylation
AKT2	down-regulates	PPARGC1A	phosphorylation
PPARGC1A	“up-regulates quantity by expression”	SLC2A4	“transcriptional regulation”
PRKAA1	“up-regulates activity”	PPARGC1A	phosphorylation
PPARGC1A	“up-regulates quantity by expression”	PPARGC1A	“transcriptional regulation”
BMP7	“up-regulates quantity by expression”	PPARGC1A	“transcriptional regulation”
PPARGC1A	down-regulates	FOXO3
PPARGC1A	up-regulates	Gluconeogenesis
AMPK	“up-regulates activity”	PPARGC1A	phosphorylation
SIRT1	“up-regulates activity”	PPARGC1A	deacetylation
BMP7	up-regulates	PPARGC1A	“transcriptional regulation”
AMPK	up-regulates	PPARGC1A	phosphorylation
PPARGC1A	up-regulates	Mitochondrial_biogenesis
SIRT1	“up-regulates quantity”	PPARGC1A	“transcriptional regulation”
STAT6	“up-regulates quantity by expression”	PPARGC1A	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	SOD2	“transcriptional regulation”
AKT1	“down-regulates activity”	PPARGC1A	phosphorylation
FOXO	down-regulates	PPARGC1A
PPARGC1A	down-regulates	FOXO
NDN	“up-regulates quantity by stabilization”	PPARGC1A	binding
PPARGC1A	“up-regulates activity”	NRF1
PPARGC1A	“up-regulates quantity by expression”	ALDOB	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nuclear Receptor transcription pathway	12	114.5×	5e-21
SUMOylation of intracellular receptors	6	96.0×	3e-09
PPARA activates gene expression	5	22.5×	2e-04
Cellular responses to stress	5	8.8×	4e-03
Cellular responses to stimuli	5	7.5×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of miRNA transcription	5	148.6×	6e-08
hormone-mediated signaling pathway	5	95.5×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

151 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	16
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

2660 predictions. Top by Δscore:

Variant	Effect	Δscore
4:23795923:AATC:A	acceptor_loss	1.0000
4:23795925:TC:T	acceptor_loss	1.0000
4:23795926:C:CC	acceptor_gain	1.0000
4:23795926:CTGA:C	acceptor_loss	1.0000
4:23801882:C:CC	acceptor_gain	1.0000
4:23812745:A:AC	donor_gain	1.0000
4:23812746:C:CC	donor_gain	1.0000
4:23824354:C:CC	acceptor_gain	1.0000
4:23824509:C:CC	acceptor_gain	1.0000
4:23828606:T:C	acceptor_gain	1.0000
4:23831555:A:AC	donor_gain	1.0000
4:23831556:C:CC	donor_gain	1.0000
4:23831576:T:TA	donor_gain	1.0000
4:23831747:ATCTT:A	acceptor_gain	1.0000
4:23831749:CTT:C	acceptor_gain	1.0000
4:23831750:TT:T	acceptor_gain	1.0000
4:23831751:TCTGC:T	acceptor_loss	1.0000
4:23831752:C:CC	acceptor_gain	1.0000
4:23831752:CT:C	acceptor_loss	1.0000
4:23831753:T:G	acceptor_loss	1.0000
4:23831755:C:CT	acceptor_gain	1.0000
4:23831756:A:T	acceptor_gain	1.0000
4:23884746:CCTTA:C	donor_loss	1.0000
4:23884747:CTTAC:C	donor_loss	1.0000
4:23884748:TTA:T	donor_loss	1.0000
4:23884749:TACC:T	donor_loss	1.0000
4:23884750:A:AC	donor_gain	1.0000
4:23884751:C:CC	donor_gain	1.0000
4:23884751:CCT:C	donor_gain	1.0000
4:23884927:GCACA:G	acceptor_gain	1.0000

AlphaMissense

5252 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:23795853:A:G	L789P	1.000
4:23795864:A:C	F785L	1.000
4:23795864:A:T	F785L	1.000
4:23795866:A:G	F785L	1.000
4:23801859:A:C	Y722D	1.000
4:23802263:C:A	G701V	1.000
4:23802264:C:G	G701R	1.000
4:23802265:A:C	F700L	1.000
4:23802265:A:T	F700L	1.000
4:23802267:A:G	F700L	1.000
4:23802275:A:G	F697S	1.000
4:23802287:A:G	L693P	1.000
4:23795845:C:G	A792P	0.999
4:23795865:A:C	F785C	0.999
4:23795865:A:G	F785S	0.999
4:23801831:G:T	A731D	0.999
4:23801832:C:G	A731P	0.999
4:23801840:G:T	A728D	0.999
4:23801855:C:G	R723P	0.999
4:23801864:A:T	I720N	0.999
4:23801870:C:T	G718D	0.999
4:23802263:C:T	G701D	0.999
4:23802264:C:A	G701C	0.999
4:23802266:A:G	F700S	0.999
4:23802274:A:C	F697L	0.999
4:23802274:A:T	F697L	0.999
4:23802276:A:G	F697L	0.999
4:23802278:C:G	R696P	0.999
4:23802323:A:T	V681D	0.999
4:23802335:C:G	R677P	0.999

dbSNP variants (sampled 300 via entrez): RS1000004727 (4:24353057 T>G), RS1000005202 (4:24181584 T>C,G), RS1000008310 (4:23900041 C>A,T), RS1000013426 (4:24063628 G>A), RS1000015334 (4:24025050 C>A), RS1000016224 (4:24294814 A>C), RS1000016811 (4:24074211 T>G), RS1000018524 (4:24224277 T>A,G), RS1000024913 (4:24220441 T>C), RS1000025514 (4:23953354 A>G), RS1000025975 (4:24430404 C>T), RS10000260 (4:24444857 C>A,G,T), RS10000295 (4:24085512 C>T), RS1000031429 (4:24068868 T>C), RS1000034108 (4:24173512 C>T)

Disease associations

OMIM: gene MIM:604517 | disease phenotypes: MIM:607426

GenCC curated gene-disease

Mondo (1): coenzyme Q10 deficiency, primary, 1 (MONDO:0011829)

Orphanet (1): Leigh syndrome with nephrotic syndrome (Orphanet:255249)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003693	Distal amyotrophy
HP:0004326	Cachexia

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST001356_36	Gout	1.000000e-07
GCST001859_22	Thiazide-induced adverse metabolic effects in hypertensive patients	5.000000e-06
GCST002114_1	Molar-incisor hypomineralization	2.000000e-06
GCST002935_22	Lead levels	8.000000e-06
GCST003075_113	Cognitive decline rate in late mild cognitive impairment	7.000000e-08
GCST003075_41	Cognitive decline rate in late mild cognitive impairment	1.000000e-07
GCST003762_8	Essential tremor	1.000000e-09
GCST003818_12	Resting heart rate	2.000000e-15
GCST005790_91	Rosacea symptom severity	4.000000e-06
GCST005803_2	Corneal astigmatism	6.000000e-07
GCST007201_217	Schizophrenia	2.000000e-09
GCST007201_464	Schizophrenia	4.000000e-09
GCST007876_1	Estimated glomerular filtration rate	3.000000e-08
GCST008058_125	Estimated glomerular filtration rate	2.000000e-16
GCST008059_38	Estimated glomerular filtration rate	3.000000e-14
GCST008526_30	Coffee consumption	3.000000e-06
GCST009277_6	Subjective response to placebo treatment in childhood asthma (change in cough/wheeze)	8.000000e-06
GCST009936_2	Venous thromboembolism	4.000000e-06
GCST010002_2	Refractive error	3.000000e-11
GCST010321_131	PR interval	5.000000e-15
GCST010796_313	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_314	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_315	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_316	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_317	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_318	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_319	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010796_320	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_321	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST012006_9	Intralaminar thalamic nuclei volume	8.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0005321	molar-incisor hypomineralization
EFO:0007710	cognitive decline measurement
EFO:0009180	rosacea severity measurement
EFO:1002040	Corneal astigmatism
EFO:0006781	coffee consumption measurement
EFO:0008344	response to placebo
EFO:0010068	respiratory symptom change measurement
EFO:0004462	PR interval
EFO:0004327	electrocardiography
EFO:0006935	thalamus volume
EFO:0004531	urate measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6116 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2970847	PPARGC1A		0.00	0
rs8192678	PPARGC1A		0.00	0
rs10213440	PPARGC1A		0.00	0

CTD chemical–gene interactions

232 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Rosiglitazone	affects response to substance, decreases expression, decreases reaction, affects reaction, affects cotreatment (+1 more)	8
Resveratrol	affects reaction, increases acetylation, decreases reaction, increases expression, increases reaction (+3 more)	8
Glucose	affects binding, increases acetylation, decreases acetylation, affects reaction, decreases expression (+4 more)	8
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation, affects cotreatment	8
bisphenol A	increases reaction, decreases reaction, affects cotreatment, affects methylation, decreases methylation (+4 more)	7
Dexamethasone	increases expression, affects cotreatment, decreases expression, affects reaction	7
dorsomorphin	decreases reaction, affects cotreatment, increases reaction, increases expression, decreases expression	5
Estradiol	affects cotreatment, decreases expression, affects binding, increases reaction, increases expression	5
Rotenone	decreases reaction, affects cotreatment, increases activity, affects reaction, increases expression (+1 more)	5
Palmitic Acid	affects cotreatment, decreases expression, decreases reaction, increases reaction, increases expression (+1 more)	5
bisphenol S	decreases expression, affects cotreatment, increases methylation, affects binding, increases reaction (+2 more)	4
Doxorubicin	decreases reaction, increases acetylation, increases expression, affects reaction, affects response to substance (+1 more)	4
Tamoxifen	decreases expression, affects cotreatment, increases expression, affects binding, decreases reaction	4
Cyclosporine	decreases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Acetylcysteine	decreases expression, decreases reaction, increases expression	3
Calcitriol	affects cotreatment, decreases activity, decreases expression, increases reaction, decreases reaction (+3 more)	3
Melatonin	affects cotreatment, increases expression, increases acetylation, decreases expression, decreases reaction	3
Metformin	increases expression, affects reaction	3
Rifampin	affects cotreatment, decreases reaction, increases expression, increases reaction, affects binding	3
Silicon Dioxide	decreases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Tobacco Smoke Pollution	decreases expression	3
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression, decreases expression, affects reaction	3
Cadmium Chloride	decreases expression, increases abundance, increases acetylation, increases expression, decreases reaction	3
PQQ Cofactor	decreases expression, decreases reaction, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
acadesine	affects cotreatment, decreases expression, decreases reaction, increases expression	2
sodium arsenite	decreases expression, increases expression	2
lithocholic acid acetate	increases reaction, affects cotreatment, increases activity, increases expression, affects binding (+1 more)	2

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037891	Binding	Stimulation of PGC1-alpha-mediated transcriptional activity of mTFA promoter in mouse C2C12 cells expressing NRF1 site after 16 hrs by luciferase reporter gene assay	Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. — J Med Chem

Cellosaurus cell lines

75 cell lines: 67 cancer cell line, 3 embryonic stem cell, 3 spontaneously immortalized cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0037	A-431	Cancer cell line	Female
CVCL_3485	A431NS	Cancer cell line	Female
CVCL_4V41	A431/TPT	Cancer cell line	Female
CVCL_A4BS	A-431-Luc2	Cancer cell line	Female
CVCL_A5P3	SEES3-1V human PPARGC1A, clone1	Embryonic stem cell	Male
CVCL_A5P4	SEES3-1V human PPARGC1A, clone2	Embryonic stem cell	Male
CVCL_A5P5	SEES3-1V human PPARGC1A, clone3	Embryonic stem cell	Male
CVCL_B1BR	Abcam A-431 ADRB2 KO	Cancer cell line	Female
CVCL_B1BS	Abcam A-431 B2M KO	Cancer cell line	Female
CVCL_B1BT	Abcam A-431 BST2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.