Mitochondrial biogenesis (Homo sapiens)

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5, 13, 18, 20, 21, 25...12, 22, 5028, 44, 47, 61126, 2734, 396838, 816416, 8133, 34, 39, 51, 53...4838, 813142, 4964, 706415, 16, 81647, 52, 6016, 81311, 166416, 41, 67, 81, 8246, 651, 29, 38, 7610741, 16cytosolnucleoplasmmitochondrial intermembrane spacemitochondrial matrixMitochondrialprotein importPOLG2 geneALAS1NAD+Zn2+ TFB1Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1HCFC1 ADPphospho-CaMKIV:CalmodulinALAS1 gene GABPA geneTFAM gene NRF2 beta-2 subunitRibC-GLUDp-AMPKheterotrimer:AMPNRF2 gamma-1 subunit CYCS gene RXRA GABPA p-T178,S539-PPARGC1A PPARGC1B TFB2Mgene:NRF1:p-PPARGC1A:NRF2NRF2 beta-1 subunit ADPp-T69,T71-ATF2p-T178,S539-PPARGC1A NAMCALM1 PPARGC1B NAMSSBP1NRF2 beta-2 subunit EPA GABPA p-T263,S266,T299-PPARGC1A SOD2 ALA TFAMgene:NRF1:NRF2:p-PPARGC1A,PPRC1NRF2 gamma-2 subunit NRF1 ATPATPATP5B gene TFB2M gene TFAM gene POLRMT geneCYCSNRF2 gamma-1 subunit Ca2+ CRTC2 NRF2 gamma-2 subunit HCFC1 GABPA p-T172-PRKAA2 NRF1 geneNRF2 gamma-1 subunit TFB1M gene TFAM(1-246)NRF2 gamma-2 subunit NCOA1 p-T180,Y182-MAPK11 TFB1M gene NRF1 ESRRASIRT4 NRF2 gamma-1 subunit p-S12,S13-CAMK4 PPRC1SSBP1 genePPRC1 CYCSTFAMgene:NRF1:NRF2:PPRC1ATPHDAC3 TFB1MATP5B geneNRF2 beta-2 subunit NRF1Palm PPARGC1A 2'-O-acetyl-ADP-riboseGLUD1 ALAS1 geneGABPA PPARGC1A gene TFAM gene TFAM genePPRC1 TFAMCYCS genePRKAB2 p-T263,S266,T299-PPARGC1A CREB1SIRT3(?-399)NRF2 gamma-1 subunit p-T263,S266,T299-PPARGC1A NRF1 PERM1 genePPARGC1BNRF2 beta-1 subunitNRF1 p-S133-CREB:CRTC1,2,3:PPARGC1A geneNRF2 gamma-2 subunit GABPA 2'-O-acetyl-ADP-riboseACSS2 NRF1 p-T178,S539-PPARGC1ANRF2 gamma-1 subunit CRTC1 NRF1 SIRT5:Zn2+ALAS1gene:NRF1:PPARGC1BNRF2 beta-1 subunit TFB2M gene POLG2(?-485)NCOA2 RibC-GLUD2 MEF2C,D:PPARGC1ARibC-GLUD1 NRF2 beta-2 subunit ACCS2,GLUD,IDH2,SOD2NRF2 beta-1 subunit NRF2 gamma-1 subunit NR1D1:heme:Corepressors:PPARGC1A geneNAD+p-T180,Y182-MAPK14 NRF1 NRF2 beta-2 subunit p-T178,S539-PPARGC1A NRF2 gamma-1 subunitSIRT3(?-399):Zn2+NRF2 beta-1 subunit NRF2 beta-2 subunit HELZ2 PPRC1 TFB1M gene p-S133-CREB1MTERFNAD+NRF2 beta-1 subunit NRF2 beta-1 subunit PPRC1 Zn2+ MEF2C NRF1 p-T178,S539-PPARGC1A phospho-p38alpha/beta/gammaMAPKESRRA geneSIRT5 PEO1 geneSIRT3(?-399) NRF2 beta-2 subunit PPARA GLUDHCFC1 AA NRF2 beta-1 subunit NRF1 NRF2 gamma-2 subunit p-S133-CREB1 p-T178,S539-PPARGC1A PRKAB1 CYCSgene:NRF1:PPARGC1BSIRT3 geneNRF2 gamma-2 subunit NRF2 gamma-2 subunit TFAMgene:NRF1:p-PPARGC1A:NRF2GABPA NRF1 NRF2 gamma-1 subunit Cristae formationPPARGC1A gene AcK-IDH2 GABPA GABPA PPARA:RXRACoactivator complexIDH2 NRF2 beta-1 subunit NRF2 beta-2 subunit NRF2 gamma-2 subunitCREBBP p-T263,S266,T299-PPARGC1A TFB2Mgene:NRF1:NRF2:HCFC1:PPRC1NAMPRKAG2 CHD9 AcK-SOD2 PPARGC1B p-T178,S539-PPARGC1A PPRC1 NRF2 gamma-2 subunit PPRC1 NRF2 gamma-1 subunit NRF2 gamma-2 subunit NCOA6 POLRMTAcK-CYCSZn2+ NRF2 beta-2 subunit CARM1 ferriheme b PERM1TFB2M gene NCOR1 HCFC1 MTERF geneNRF2NR1D1 TBL1X LINA p-T263,S266,T299-PPARGC1A GLUD2 SIRT4:Zn2+NRF2 beta-2 subunit AcK-ACSS2 p-T178,S539-PPARGC1A NRF1 NRF2 beta-1 subunit PPARGC1A geneSMARCD3 ADPPRKAG1 TFB2M geneMAPK12 NRF2 gamma-2 subunit GABPA Ack-ACCS2,AcK-GLUD,AcK-IDH2,Ack-SOD2TBL1XR1 p-T263,S266,T299-PPARGC1A NRF2 beta-1 subunit p-PPARGC1ATGS1 GABPA NRF2 beta-2 subunit NRF2 gamma-1 subunit HCFC1AMP NRF1 TFB1Mgene:NRF1:NRF2:HCFC1:PPRC1ATP5Bgene:NRF1:PPARGC1BATP5BTFB1Mgene:NRF1:p-PPARGC1A:NRF2CRTC3 TFB2Mp-T263,S266,T299-PPARGC1A MED1 PRKAG3 TFB1M geneTFB2Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1GLUD AcK-GLUD Peroxisome Proliferator Receptor Element (PPRE) GABPAp-T263,S266,T299-PPARGC1APEO1PPARGC1AMEF2D 16, 81457, 14313, 9, 19, 37, 56...1, 16, 38, 81242432436, 7916, 38, 76, 8187, 14451, 16, 38, 8136, 7923812, 11, 17, 30, 40...231, 16, 38, 76, 81


Description

Mitochondrial biogenesis and remodeling occur in response to exercise and redox state (reviewed in Scarpulla et al. 2012, Handy and Loscalzo 2012, Piantadosi and Suliman 2012, Scarpulla 2011, Wenz et al. 2011, Bo et al. 2010, Jornayvaz and Shulman 2010, Ljubicic et al. 2010, Hock and Kralli 2009, Canto and Auwerx 2009, Lin 2009, Scarpulla 2008, Ventura-Clapier et al. 2008). It is hypothesized that calcium influx and energy depletion are the signals that initiate changes in gene expression leading to new mitochondrial proteins. Energy depletion causes a reduction in ATP and an increase in AMP which activates AMPK. AMPK in turn phosphorylates the coactivator PGC-1alpha (PPARGC1A), one of the master regulators of mitochondrial biosynthesis. Likewise, p38 MAPK is activated by muscle contraction (possibly via calcium and CaMKII) and phosphorylates PGC-1alpha. CaMKIV responds to intracellular calcium by phosphorylating CREB, which activates expression of PGC-1alpha.
Deacetylation of PGC-1alpha by SIRT1 may also play a role in activation (Canto et al. 2009, Gurd et al. 2011), however Sirt11 deacetylation of Ppargc1a in mouse impacted genes related to glucose metabolism rather than mitochondrial biogenesis (Rodgers et al. 2005) and mice lacking SIRT1 in muscle had normal levels of mitochondrial biogenesis in response to exercise (Philp et al. 2011) so the role of deacetylation is not fully defined. PGC-1beta and PPRC appear to act similarly to PGC-1alpha but they have not been as well studied.
Phosphorylated PGC-1alpha does not bind DNA directly but instead interacts with other transcription factors, notably NRF1 and NRF2 (via HCF1). NRF1 and NRF2 together with PGC-1alpha activate the transcription of nuclear-encoded, mitochondrially targeted proteins such as TFB2M, TFB1M, and TFAM. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1592230
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114736view16:22, 25 January 2021ReactomeTeamReactome version 75
113180view11:24, 2 November 2020ReactomeTeamReactome version 74
112407view15:34, 9 October 2020ReactomeTeamReactome version 73
101311view11:20, 1 November 2018ReactomeTeamreactome version 66
100848view20:51, 31 October 2018ReactomeTeamreactome version 65
100389view19:25, 31 October 2018ReactomeTeamreactome version 64
99936view16:09, 31 October 2018ReactomeTeamreactome version 63
99492view14:43, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93816view13:38, 16 August 2017ReactomeTeamreactome version 61
93362view11:21, 9 August 2017ReactomeTeamreactome version 61
87949view13:05, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86444view09:18, 11 July 2016ReactomeTeamreactome version 56
83099view09:58, 18 November 2015ReactomeTeamVersion54
81431view12:57, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseMetaboliteCHEBI:76279 (ChEBI)
AA MetaboliteCHEBI:15843 (ChEBI)
ACCS2,GLUD,IDH2,SOD2ComplexR-HSA-5688291 (Reactome)
ACSS2 ProteinQ9NR19 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
ALAS1 gene:NRF1:PPARGC1BComplexR-HSA-2466384 (Reactome)
ALAS1 gene ProteinENSG00000023330 (Ensembl)
ALAS1 geneGeneProductENSG00000023330 (Ensembl)
ALAS1ProteinP13196 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
ATP5B gene:NRF1:PPARGC1BComplexR-HSA-2466375 (Reactome)
ATP5B gene ProteinENSG00000110955 (Ensembl)
ATP5B geneGeneProductENSG00000110955 (Ensembl)
ATP5BProteinP06576 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AcK-ACSS2 ProteinQ9NR19 (Uniprot-TrEMBL)
AcK-CYCSProteinP99999 (Uniprot-TrEMBL)
AcK-GLUD R-HSA-5688301 (Reactome)
AcK-IDH2 ProteinP48735 (Uniprot-TrEMBL)
AcK-SOD2 ProteinP04179 (Uniprot-TrEMBL)
Ack-ACCS2,AcK-GLUD,AcK-IDH2,Ack-SOD2ComplexR-HSA-5688306 (Reactome)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CRTC1 ProteinQ6UUV9 (Uniprot-TrEMBL)
CRTC2 ProteinQ53ET0 (Uniprot-TrEMBL)
CRTC3 ProteinQ6UUV7 (Uniprot-TrEMBL)
CYCS gene:NRF1:PPARGC1BComplexR-HSA-2466382 (Reactome)
CYCS gene ProteinENSG00000172115 (Ensembl)
CYCS geneGeneProductENSG00000172115 (Ensembl)
CYCSProteinP99999 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Cristae formationPathwayR-HSA-8949613 (Reactome) Cristae are invaginations of the inner mitochondrial membrane that extend into the matrix and are lined with cytochrome complexes and F1Fo ATP synthase complexes. Cristae increase the surface area of the inner membranes allowing greater numbers of respiratory complexes. Cristae are also believed to serve as "proton pockets" to generate localized regions of higher membrane potential. The steps in the biogenesis of cristae are not yet completely elucidated (reviewed in Zick et al. 2009) but the formation of the Mitochondrial Contact Site and Cristae Organizing System (MICOS, formerly also known as MINOS, reviewed in Rampelt et al. 2016, Kozjak-Pavlovic 2016, van der Laan et al. 2016) and localized concentrations of cardiolipin are known to define the inward curvature of the inner membrane at the bases of cristae. MICOS also links these regions of the inner membrane with complexes (the SAM complex and, in fungi, the TOM complex) embedded in the outer membrane. CHCHD3 (MIC19) and IMMT (MIC60) subunits of MICOS also interact with OPA1 at the inner membrane (Darshi et al. 2011, Glytsou et al. 2016).
Formation of dimers or oligomers of the F1Fo ATP synthase complex causes extreme curvature of the inner membrane at the apices of cristae (reviewed in Seelert and Dencher 2011, Habersetzer et al. 2013). Defects in either MICOS or F1Fo ATP synthase oligomerization produce abnormal mitochondrial morphologies.
EPA MetaboliteCHEBI:28364 (ChEBI)
ESRRA geneGeneProductENSG00000173153 (Ensembl)
ESRRAProteinP11474 (Uniprot-TrEMBL)
GABPA ProteinQ06546 (Uniprot-TrEMBL)
GABPA geneGeneProductENSG00000154727 (Ensembl)
GABPAProteinQ06546 (Uniprot-TrEMBL)
GLUD R-HSA-5687782 (Reactome)
GLUD1 ProteinP00367 (Uniprot-TrEMBL)
GLUD2 ProteinP49448 (Uniprot-TrEMBL)
GLUDComplexR-HSA-5687782 (Reactome)
HCFC1 ProteinP51610 (Uniprot-TrEMBL)
HCFC1ProteinP51610 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
IDH2 ProteinP48735 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
MAPK12 ProteinP53778 (Uniprot-TrEMBL)
MED1 ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MEF2C ProteinQ06413 (Uniprot-TrEMBL)
MEF2C,D:PPARGC1AComplexR-HSA-1605560 (Reactome)
MEF2D ProteinQ14814 (Uniprot-TrEMBL)
MTERF geneGeneProductENSG00000127989 (Ensembl)
MTERFProteinQ99551 (Uniprot-TrEMBL)
Mitochondrial protein importPathwayR-HSA-1268020 (Reactome) A human mitochondrion contains about 1500 proteins, more than 99% of which are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondrion. Proteins are targeted to four locations (outer membrane, intermembrane space, inner membrane, and matrix) and must be sorted accordingly (reviewed in Kutik et al. 2007, Milenkovic et al. 2007, Bolender et al. 2008, Endo and Yamano 2009). Newly synthesized proteins are transported from the cytosol across the outer membrane by the TOMM40:TOMM70 complex. Proteins that contain presequences first interact with the TOMM20 subunit of the complex while proteins that contain internal targeting elements first interact with the TOMM70 subunit. After initial interaction the protein is conducted across the outer membrane by TOMM40 subunits. In yeast some proteins such as Aco1, Atp1, Cit1, Idh1, and Atp2 have both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009).
After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex.
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
NCOA1 ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 ProteinQ15596 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NR1D1 ProteinP20393 (Uniprot-TrEMBL)
NR1D1:heme:Corepressors:PPARGC1A geneComplexR-HSA-5663272 (Reactome)
NRF1 ProteinQ16656 (Uniprot-TrEMBL)
NRF1 geneGeneProductENSG00000106459 (Ensembl)
NRF1ProteinQ16656 (Uniprot-TrEMBL)
NRF2 beta-1 subunit ProteinQ06547-1 (Uniprot-TrEMBL)
NRF2 beta-1 subunitProteinQ06547-1 (Uniprot-TrEMBL)
NRF2 beta-2 subunit ProteinQ06547-2 (Uniprot-TrEMBL)
NRF2 beta-2 subunitProteinQ06547-2 (Uniprot-TrEMBL)
NRF2 gamma-1 subunit ProteinQ06547-3 (Uniprot-TrEMBL)
NRF2 gamma-1 subunitProteinQ06547-3 (Uniprot-TrEMBL)
NRF2 gamma-2 subunit ProteinQ06547-4 (Uniprot-TrEMBL)
NRF2 gamma-2 subunitProteinQ06547-4 (Uniprot-TrEMBL)
NRF2ComplexR-HSA-1592226 (Reactome)
PEO1 geneGeneProductENSG00000107815 (Ensembl)
PEO1ProteinQ96RR1 (Uniprot-TrEMBL)
PERM1 geneGeneProductENSG00000187642 (Ensembl)
PERM1ProteinQ5SV97 (Uniprot-TrEMBL)
POLG2 geneGeneProductENSG00000256525 (Ensembl)
POLG2(?-485)ProteinQ9UHN1 (Uniprot-TrEMBL)
POLRMT geneGeneProductENSG00000099821 (Ensembl)
POLRMTProteinO00411 (Uniprot-TrEMBL)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1A gene ProteinENSG00000109189 (Ensembl)
PPARGC1A geneGeneProductENSG00000109189 (Ensembl)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1B ProteinQ86YN6 (Uniprot-TrEMBL)
PPARGC1BProteinQ86YN6 (Uniprot-TrEMBL)
PPRC1 ProteinQ5VV67 (Uniprot-TrEMBL)
PPRC1ProteinQ5VV67 (Uniprot-TrEMBL)
PRKAB1 ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
Palm MetaboliteCHEBI:15756 (ChEBI)
Peroxisome Proliferator Receptor Element (PPRE) R-ALL-422139 (Reactome) Peroxisome proliferator receptor elements bind heterodimers containing a peroxisome proliferator receptor and a retinoic acid receptor. The consensus sequence is TGAMCTTTGNCCTAGWTYYG.
RXRA ProteinP19793 (Uniprot-TrEMBL)
RibC-GLUD1 ProteinP00367 (Uniprot-TrEMBL)
RibC-GLUD2 ProteinP49448 (Uniprot-TrEMBL)
RibC-GLUDComplexR-HSA-5688267 (Reactome)
SIRT3 geneGeneProductENSG00000142082 (Ensembl)
SIRT3(?-399) ProteinQ9NTG7 (Uniprot-TrEMBL)
SIRT3(?-399):Zn2+ComplexR-HSA-5688322 (Reactome)
SIRT3(?-399)ProteinQ9NTG7 (Uniprot-TrEMBL)
SIRT4 ProteinQ9Y6E7 (Uniprot-TrEMBL)
SIRT4:Zn2+ComplexR-HSA-5688269 (Reactome)
SIRT5 ProteinQ9NXA8 (Uniprot-TrEMBL)
SIRT5:Zn2+ComplexR-HSA-5688288 (Reactome)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
SOD2 ProteinP04179 (Uniprot-TrEMBL)
SSBP1 geneGeneProductENSG00000106028 (Ensembl)
SSBP1ProteinQ04837 (Uniprot-TrEMBL)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TFAM gene:NRF1:NRF2:PPRC1ComplexR-HSA-1592221 (Reactome)
TFAM gene:NRF1:NRF2:p-PPARGC1A,PPRC1ComplexR-HSA-2466363 (Reactome)
TFAM gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466379 (Reactome)
TFAM gene ProteinENSG00000108064 (Ensembl)
TFAM geneGeneProductENSG00000108064 (Ensembl)
TFAM(1-246)ProteinQ00059 (Uniprot-TrEMBL)
TFAMProteinQ00059 (Uniprot-TrEMBL)
TFB1M gene:NRF1:NRF2:HCFC1:PPRC1ComplexR-HSA-2466381 (Reactome)
TFB1M gene:NRF1:NRF2:p-PPARGC1A,PPRC1ComplexR-HSA-2466390 (Reactome)
TFB1M gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466393 (Reactome)
TFB1M gene ProteinENSG00000029639 (Ensembl)
TFB1M geneGeneProductENSG00000029639 (Ensembl)
TFB1MProteinQ8WVM0 (Uniprot-TrEMBL)
TFB2M gene:NRF1:NRF2:HCFC1:PPRC1ComplexR-HSA-2466365 (Reactome)
TFB2M gene:NRF1:NRF2:p-PPARGC1A,PPRC1ComplexR-HSA-2466378 (Reactome)
TFB2M gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466376 (Reactome)
TFB2M gene ProteinENSG00000162851 (Ensembl)
TFB2M geneGeneProductENSG00000162851 (Ensembl)
TFB2MProteinQ9H5Q4 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
ferriheme b MetaboliteCHEBI:36144 (ChEBI)
p-AMPK heterotrimer:AMPComplexR-HSA-2151198 (Reactome)
p-PPARGC1AComplexR-HSA-1592227 (Reactome)
p-S12,S13-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB:CRTC1,2,3:PPARGC1A geneComplexR-HSA-8931947 (Reactome)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T178,S539-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T178,S539-PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T263,S266,T299-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T263,S266,T299-PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
phospho-CaMK IV:CalmodulinComplexR-HSA-111904 (Reactome)
phospho-p38

alpha/beta/gamma

MAPK
ComplexR-HSA-448858 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseArrowR-HSA-5688289 (Reactome)
2'-O-acetyl-ADP-riboseArrowR-HSA-5688294 (Reactome)
ACCS2,GLUD,IDH2,SOD2ArrowR-HSA-5688289 (Reactome)
ADPArrowR-HSA-111912 (Reactome)
ADPArrowR-HSA-1592233 (Reactome)
ADPArrowR-HSA-1592244 (Reactome)
ALAS1 gene:NRF1:PPARGC1BArrowR-HSA-1592238 (Reactome)
ALAS1 gene:NRF1:PPARGC1BArrowR-HSA-1592245 (Reactome)
ALAS1 geneR-HSA-1592238 (Reactome)
ALAS1 geneR-HSA-1592245 (Reactome)
ALAS1ArrowR-HSA-1592238 (Reactome)
ATP5B gene:NRF1:PPARGC1BArrowR-HSA-1592247 (Reactome)
ATP5B gene:NRF1:PPARGC1BArrowR-HSA-2466369 (Reactome)
ATP5B geneR-HSA-1592247 (Reactome)
ATP5B geneR-HSA-2466369 (Reactome)
ATP5BArrowR-HSA-1592247 (Reactome)
ATPR-HSA-111912 (Reactome)
ATPR-HSA-1592233 (Reactome)
ATPR-HSA-1592244 (Reactome)
AcK-CYCSR-HSA-5688294 (Reactome)
Ack-ACCS2,AcK-GLUD,AcK-IDH2,Ack-SOD2R-HSA-5688289 (Reactome)
CREB1R-HSA-111912 (Reactome)
CYCS gene:NRF1:PPARGC1BArrowR-HSA-1592231 (Reactome)
CYCS gene:NRF1:PPARGC1BArrowR-HSA-2466370 (Reactome)
CYCS geneR-HSA-1592231 (Reactome)
CYCS geneR-HSA-2466370 (Reactome)
CYCSArrowR-HSA-1592231 (Reactome)
CYCSArrowR-HSA-5688294 (Reactome)
ESRRA geneR-HSA-1605428 (Reactome)
ESRRAArrowR-HSA-1592231 (Reactome)
ESRRAArrowR-HSA-1592238 (Reactome)
ESRRAArrowR-HSA-1592247 (Reactome)
ESRRAArrowR-HSA-1605428 (Reactome)
ESRRAArrowR-HSA-8940309 (Reactome)
GABPA geneR-HSA-1592234 (Reactome)
GABPAArrowR-HSA-1592234 (Reactome)
GABPAR-HSA-1592240 (Reactome)
GLUDR-HSA-5688276 (Reactome)
HCFC1R-HSA-1592250 (Reactome)
HCFC1R-HSA-2466367 (Reactome)
MEF2C,D:PPARGC1AArrowR-HSA-1368140 (Reactome)
MTERF geneR-HSA-1592251 (Reactome)
MTERFArrowR-HSA-1592251 (Reactome)
NAD+R-HSA-5688276 (Reactome)
NAD+R-HSA-5688289 (Reactome)
NAD+R-HSA-5688294 (Reactome)
NAMArrowR-HSA-5688276 (Reactome)
NAMArrowR-HSA-5688289 (Reactome)
NAMArrowR-HSA-5688294 (Reactome)
NR1D1:heme:Corepressors:PPARGC1A geneTBarR-HSA-1368140 (Reactome)
NRF1 geneR-HSA-1592242 (Reactome)
NRF1ArrowR-HSA-1592242 (Reactome)
NRF1R-HSA-1592236 (Reactome)
NRF1R-HSA-1592245 (Reactome)
NRF1R-HSA-1592249 (Reactome)
NRF1R-HSA-1592250 (Reactome)
NRF1R-HSA-2466367 (Reactome)
NRF1R-HSA-2466369 (Reactome)
NRF1R-HSA-2466370 (Reactome)
NRF1R-HSA-2466391 (Reactome)
NRF1R-HSA-2466392 (Reactome)
NRF2 beta-1 subunitR-HSA-1592240 (Reactome)
NRF2 beta-2 subunitR-HSA-1592240 (Reactome)
NRF2 gamma-1 subunitR-HSA-1592240 (Reactome)
NRF2 gamma-2 subunitR-HSA-1592240 (Reactome)
NRF2ArrowR-HSA-1592234 (Reactome)
NRF2ArrowR-HSA-1592235 (Reactome)
NRF2ArrowR-HSA-1592239 (Reactome)
NRF2ArrowR-HSA-1592240 (Reactome)
NRF2ArrowR-HSA-1592241 (Reactome)
NRF2ArrowR-HSA-1592243 (Reactome)
NRF2ArrowR-HSA-1592251 (Reactome)
NRF2R-HSA-1592236 (Reactome)
NRF2R-HSA-1592249 (Reactome)
NRF2R-HSA-1592250 (Reactome)
NRF2R-HSA-2466367 (Reactome)
NRF2R-HSA-2466391 (Reactome)
NRF2R-HSA-2466392 (Reactome)
PEO1 geneR-HSA-1592239 (Reactome)
PEO1ArrowR-HSA-1592239 (Reactome)
PERM1 geneR-HSA-8940309 (Reactome)
PERM1ArrowR-HSA-8940309 (Reactome)
POLG2 geneR-HSA-1592235 (Reactome)
POLG2(?-485)ArrowR-HSA-1592235 (Reactome)
POLRMT geneR-HSA-1592243 (Reactome)
POLRMTArrowR-HSA-1592243 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-1592238 (Reactome)
PPARGC1A geneR-HSA-1368140 (Reactome)
PPARGC1AArrowR-HSA-1368140 (Reactome)
PPARGC1AR-HSA-1592233 (Reactome)
PPARGC1AR-HSA-1592244 (Reactome)
PPARGC1BR-HSA-1592245 (Reactome)
PPARGC1BR-HSA-2466369 (Reactome)
PPARGC1BR-HSA-2466370 (Reactome)
PPRC1R-HSA-1592249 (Reactome)
PPRC1R-HSA-1592250 (Reactome)
PPRC1R-HSA-2466367 (Reactome)
R-HSA-111912 (Reactome) The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, making it a point of potential convergence for multiple intracellular signaling cascades. Work in neurons has indicated that physiologic synaptic stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathway that dominates early signaling to CREB.
R-HSA-1368140 (Reactome) The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPARGC1A protein is located in the nucleus where it coactivates transcription.
R-HSA-1592229 (Reactome) TFAM is encoded in the nucleus, synthesized as a precursor in the cytosol, and imported into the mitochondrial matrix (presumably by the SAM50 complex and the TIM23:PAM complex, reviewed in van der Laan et al. 2006). In the mitochondrial matrix TFAM binds the light strand promoter of mitochondrial DNA and regulates transcription.
R-HSA-1592231 (Reactome) The gene encoding cytochrome c (CYCS) is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the precursor of cytochrome c, which is then imported into the mitochodrial matrix and associates with the matrix face of the inner membrane.
R-HSA-1592232 (Reactome) The TFB1M gene is transcribed to yield mRNA and the mRNA is translated to yield precursor protein in the cytosol (McCulloch et al. 2002, Gleyzer et al. 2005, Vercauteren et al. 2008, Cotney et al. 2009). The TFB1M precursor is then imported into the mitochondiral matrix where it acts as both a 12S RNA methylase and a DNA-binding transcription factor (inferred from mouse in Metodiev et al. 2009).
R-HSA-1592233 (Reactome) As inferred from mouse, p38 MAPK phosphorylates PGC-1alpha (PPARGC1A). Because p38 MAPK is responsive to intracellular calcium, this reaction may couple exercise to mitochondrial biogenesis.
Phosphorylated p38 MAPK is found in the nucleus (Chan et al. 2004, http://www.cellsignal.com/products/4511.html, inferred from mouse in Blanco-Aparicio et al. 1999). p38 MAPK alpha, beta, and gamma (but not delta) are found in skeletal muscle (Jiang et al. 1997). PPARGC1A (PGC-1alpha) is predominantly nuclear (Knutti et al. 2001). As inferred from rat, PPARGC1A may translocate from the cytosol to the nucleus during activation (Wright et al. 2007).
R-HSA-1592234 (Reactome) The GABPA (NRF2 alpha subunit) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Two subunits of GABPA bind two subunits of GABPB1 to form Nuclear respiratory factor 2 (NRF2).
R-HSA-1592235 (Reactome) The POLG2 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein.POLG2 is imported into the mitochondrial matrix where it functions in DNA replication.
R-HSA-1592236 (Reactome) PGC-1alpha (PPARGC1A) binds NRF1 and coactivates genes regulated by NRF1 (Gleyzer et al. 2005, Vercauteren et al. 2008, inferred from mouse in Wu et al. 1999).
R-HSA-1592238 (Reactome) The ALAS1 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. The ALAS1 precursor is imported into the mitochodrial matrix where it catalyzes the synthesis of 5-aminolevulinate from glycine and succinyl-CoA as part of heme biosynthesis.
R-HSA-1592239 (Reactome) The PEO1 (TWINKLE) gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. PEO1 is imported into the mitochondrial matrix where it may play a role in DNA replication.
R-HSA-1592240 (Reactome) Five subunits (alpha, beta-1, beta-2, gamma-1, gamma-2) assemble to form the DNA-binding transcription factor NRF2 (Gugneja et al. 1995).
R-HSA-1592241 (Reactome) The SSBP1 (mtSSB) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. The precursor SSBP1 is imported into the mitochondiral matrix where it binds single-stranded DNA.
R-HSA-1592242 (Reactome) The NRF1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. NRF1 protein is located in the nucleus where it regulates transcription.
R-HSA-1592243 (Reactome) The POLRMT (mitochondrial RNA polymerase) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield POLRMT precursor, which is then imported into the mitochondria matrix. In the mitochondrial matrix POLRMT transcribes mitochondrial DNA.
R-HSA-1592244 (Reactome) As inferred from mouse, AMPK is activated by AMP and phosphorylates PGC-1alpha (PPARGC1A). It is hypothesized that this reaction connects energy depletion (low ATP, high AMP) to mitochondrial biogenesis (activation of PGC-1alpha).
R-HSA-1592245 (Reactome) As inferred from mouse, PGC-1beta (PPARGC1B) binds NRF1 and coactivates genes regulated by NRF1.
R-HSA-1592246 (Reactome) The TFAM gene is transcribed in the nucleus to yield mRNA and the mRNA is translated to yield precursor protein in the cytosol.
R-HSA-1592247 (Reactome) The ATP5B (ATP synthase beta subunit) gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the ATP5B precursor, which is then imported into the mitochondrial matrix. ATP5B is a peripheral membrane protein located at the matrix face of the inner membrane within the ATP synthase complex (reviewed in Leyva et al. 2003).
R-HSA-1592249 (Reactome) PRC (PPRC1) binds NRF1 and coactivates genes regulated by NRF1 (Andersson and Scarpulla 2001, Vercauteren et al. 2008).
R-HSA-1592250 (Reactome) Both PRC (PPRC1) and NRF2 bind HCF1 (Vercauteren et al. 2008). PRC, like PGC-1alpha, can coactivate NRF2 (Gleyzer et al. 2005).
R-HSA-1592251 (Reactome) The mTERF gene is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. mTERF is imported into the mitochondrial matrix where it plays a role in terminating transcription.
R-HSA-1592252 (Reactome) The TFB2M gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The TFB2M precursor is then imported into the mitochondiral matrix where it acts as both a 12S RNA methylase and a DNA-binding transcription factor (Gleyzer et al. 2005, Cotney and Shadel 2006, Vercauteren et al. 2008).
R-HSA-1605428 (Reactome) The ERR1 (ERRalpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. ERR1 is a nuclear receptor that interacts with PPARGC1A (PGC-1alpha) and regulates energy metabolism.
R-HSA-1605535 (Reactome) The SIRT3 gene is transcribed to yield mRNA and the mRNA is translated in the cytosol to yield precursor protein. SIRT3 is imported into the mitochondrial matrix where it deacetylates, and hence activates, target proteins
R-HSA-2466367 (Reactome) Both PRC (PPRC1) and NRF2 bind HCF1 (Vercauteren et al. 2008). PRC, like PGC-1alpha, can coactivate NRF2 (Gleyzer et al. 2005).
R-HSA-2466369 (Reactome) As inferred from mouse, PGC-1beta (PPARGC1B) binds NRF1 and coactivates genes regulated by NRF1.
R-HSA-2466370 (Reactome) As inferred from mouse, PGC-1beta (PPARGC1B) binds NRF1 and coactivates genes regulated by NRF1.
R-HSA-2466391 (Reactome) PRC (PPRC1) binds NRF1 and coactivates genes regulated by NRF1 (Andersson and Scarpulla 2001, Vercauteren et al. 2008).
R-HSA-2466392 (Reactome) PGC-1alpha (PPARGC1A) binds NRF1 and coactivates genes regulated by NRF1 (Gleyzer et al. 2005, Vercauteren et al. 2008, inferred from mouse in Wu et al. 1999).
R-HSA-5688276 (Reactome) Sirtuin 4 (SIRT4) is a mitochondrial ADP-ribosyltransferase and deacetylase. It uses NAD+ to ADP-ribosylate glutamate dehydrogenase (GLUD), reducing its enzyme activity by at least 50%, leading to reduced insulin secretion in pancreatic beta cells (Haigis et al. 2006, Ahuja et al. 2007).
R-HSA-5688289 (Reactome) Sirtuin 3 (SIRT3) is the most extensively studied of the mitochondrial sirtuins. It deacetylates and thereby activates Acetyl-CoA synthetase 2 (ACCS2), Glutamate dehydrogenase (GLUD), Isocitrate dehydrogenase 2 (IDH2) and Superoxide dismutase 2 (SOD2) (Schwer et al. 2006, Lombard et al. 2007, Schlicker et al. 2008, Tao et al. 2010).
R-HSA-5688294 (Reactome) Sirtuin 5 has been shown to deacetylate Cytochrome C in the the mitochondrial intermembrane space (Schlicker et al. 2008). The functional significance of this is unknown (Bao & Sack 2010).
R-HSA-8940309 (Reactome) As inferred from the mouse homolog, the PERM1 gene is transcribed to yield mRNA, the mRNA is translated to yield protein. The PERM1 gene is expressed selectively in muscle where it is activated by PPARGC1A via the estrogen receptor ESRRA, which binds regulatory regions of the PERM1 gene. PERM1 selectively regulates mitochondrial biogenesis and oxidative function.
RibC-GLUDArrowR-HSA-5688276 (Reactome)
SIRT3 geneR-HSA-1605535 (Reactome)
SIRT3(?-399):Zn2+mim-catalysisR-HSA-5688289 (Reactome)
SIRT3(?-399)ArrowR-HSA-1605535 (Reactome)
SIRT4:Zn2+mim-catalysisR-HSA-5688276 (Reactome)
SIRT5:Zn2+mim-catalysisR-HSA-5688294 (Reactome)
SSBP1 geneR-HSA-1592241 (Reactome)
SSBP1ArrowR-HSA-1592241 (Reactome)
TFAM gene:NRF1:NRF2:PPRC1ArrowR-HSA-1592249 (Reactome)
TFAM gene:NRF1:NRF2:p-PPARGC1A,PPRC1ArrowR-HSA-1592246 (Reactome)
TFAM gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-2466391 (Reactome)
TFAM geneR-HSA-1592246 (Reactome)
TFAM geneR-HSA-1592249 (Reactome)
TFAM geneR-HSA-2466391 (Reactome)
TFAM(1-246)ArrowR-HSA-1592246 (Reactome)
TFAM(1-246)R-HSA-1592229 (Reactome)
TFAMArrowR-HSA-1592229 (Reactome)
TFB1M gene:NRF1:NRF2:HCFC1:PPRC1ArrowR-HSA-1592250 (Reactome)
TFB1M gene:NRF1:NRF2:p-PPARGC1A,PPRC1ArrowR-HSA-1592232 (Reactome)
TFB1M gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-1592236 (Reactome)
TFB1M geneR-HSA-1592232 (Reactome)
TFB1M geneR-HSA-1592236 (Reactome)
TFB1M geneR-HSA-1592250 (Reactome)
TFB1MArrowR-HSA-1592232 (Reactome)
TFB2M gene:NRF1:NRF2:HCFC1:PPRC1ArrowR-HSA-2466367 (Reactome)
TFB2M gene:NRF1:NRF2:p-PPARGC1A,PPRC1ArrowR-HSA-1592252 (Reactome)
TFB2M gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-2466392 (Reactome)
TFB2M geneR-HSA-1592252 (Reactome)
TFB2M geneR-HSA-2466367 (Reactome)
TFB2M geneR-HSA-2466392 (Reactome)
TFB2MArrowR-HSA-1592252 (Reactome)
p-AMPK heterotrimer:AMPmim-catalysisR-HSA-1592244 (Reactome)
p-PPARGC1AArrowR-HSA-1368140 (Reactome)
p-PPARGC1AArrowR-HSA-1592234 (Reactome)
p-PPARGC1AArrowR-HSA-1592242 (Reactome)
p-PPARGC1AArrowR-HSA-1605428 (Reactome)
p-PPARGC1AArrowR-HSA-1605535 (Reactome)
p-PPARGC1AR-HSA-1592236 (Reactome)
p-PPARGC1AR-HSA-2466391 (Reactome)
p-PPARGC1AR-HSA-2466392 (Reactome)
p-S133-CREB1ArrowR-HSA-111912 (Reactome)
p-S133-CREB:CRTC1,2,3:PPARGC1A geneArrowR-HSA-1368140 (Reactome)
p-T178,S539-PPARGC1AArrowR-HSA-1592244 (Reactome)
p-T263,S266,T299-PPARGC1AArrowR-HSA-1592233 (Reactome)
p-T69,T71-ATF2ArrowR-HSA-1368140 (Reactome)
phospho-CaMK IV:Calmodulinmim-catalysisR-HSA-111912 (Reactome)
phospho-p38

alpha/beta/gamma

MAPK
mim-catalysisR-HSA-1592233 (Reactome)
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