Mitochondrial biogenesis (Homo sapiens)

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4, 7, 8, 11, 22...6210, 5819, 6014, 566, 9, 40, 51624221, 3827, 37, 581810, 13, 25, 41572, 1227, 581, 20, 27, 36, 5818, 592, 3, 5, 12, 44...1810, 581624, 28, 6327, 581813, 271813, 27mitochondrial matrixnucleoplasmcytosolmitochondrial intermembrane spaceHCFC1 NRF2 beta-2 subunit CYCS gene CREBBP TFB2M geneNRF2 gamma-1 subunitESRRAferriheme b NRF2 beta-2 subunit NRF2 gamma-1 subunitATP5BATPEPA PPARGC1A gene Palm NR1D1 PPARA SIRT3(?-399)RXRA p-T263,S266,T299-PPARGC1A TFAMNRF2 beta-2 subunit POLG2 geneTFB1Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1TFB2M gene TBL1X TFAMgene:NRF1:p-PPARGC1A:NRF2p-T69,T71-ATF2SSBP1 geneNRF1p-S133-CREB1NRF1 ATPTFB1M gene TFAM gene NCOA1 PRKAG3 ADPMED1 TBL1XR1 TFAMgene:NRF1:NRF2:PPRC1AMP POLRMTHDAC3 GABPA GABPA geneSMARCD3 NRF2 gamma-2 subunitATP5B geneNRF2 beta-1 subunit GABPANR1D1:heme:Corepressors:PPARGC1A geneNRF2 gamma-1 subunitNRF2 beta-2 subunitPPARGC1A CARM1 TFB2M gene PEO1SSBP1CYCSgene:NRF1:PPARGC1BNRF2 beta-2 subunit PRKAG1 NRF2 gamma-1 subunitNCOR1 NRF1 NRF2 beta-1 subunit TFAMgene:NRF1:NRF2:p-PPARGC1A,PPRC1SIRT3 geneNRF2 beta-1 subunit NRF1 ALA phospho-p38alpha/beta/gammaMAPKNRF2 beta-2 subunit p-T263,S266,T299-PPARGC1AALAS1gene:NRF1:PPARGC1BTFB1Mgene:NRF1:p-PPARGC1A:NRF2p-T178,S539-PPARGC1AHCFC1ATP5B gene NRF1 PPARGC1B p-T263,S266,T299-PPARGC1A ADPNCOA2 TFB2Mgene:NRF1:p-PPARGC1A:NRF2PRKAG2 PPARGC1BGABPA TFAM geneTFB1Mgene:NRF1:NRF2:HCFC1:PPRC1NRF2 gamma-2 subunitNRF2 beta-1 subunitp-T172-PRKAA2 TFAM gene MTERFPPRC1 PRKAB1 p-T178,S539-PPARGC1ANRF2 gamma-2 subunitTFB1MNRF2 gamma-1 subunitALAS1 gene NRF1 geneNCOA6 p-AMPKheterotrimer:AMPNRF2 gamma-2 subunitMEF2C PPRC1 ESRRA geneNRF2 beta-1 subunit NRF2PRKAB2 TFB2Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1NRF1 p-T178,S539-PPARGC1AGABPA CYCS geneNRF2 beta-1 subunit MEF2C,D:PPARGC1ATFB1M gene ATP5Bgene:NRF1:PPARGC1BLINA PPARGC1B NRF2 beta-2 subunit TFAM(1-246)NRF1 PPRC1NRF2 beta-2 subunit MEF2D NRF2 gamma-2 subunitGABPA TFB2MMitochondrialprotein importHCFC1 NRF2 gamma-1 subunitPPARGC1AGABPA TGS1 NRF1 PPRC1 HELZ2 GABPA NRF2 gamma-2 subunitNRF2 gamma-2 subunitPPARGC1B POLG2(?-485)NRF2 beta-1 subunit TFB1M geneMTERF genePOLRMTPEO1 geneGABPA NRF2 gamma-2 subunitp-T178,S539-PPARGC1AALAS1 geneNRF1 CYCSAA p-PPARGC1ANRF2 gamma-1 subunitNRF1 PPARGC1A geneCHD9 p-T263,S266,T299-PPARGC1A NRF2 gamma-1 subunitALAS1TFB2Mgene:NRF1:NRF2:HCFC1:PPRC1NRF2 beta-1 subunit PPARA:RXRACoactivator complex10, 13, 27, 41, 5810, 13, 27, 586210, 13, 27, 58545827, 5833, 6310, 27, 41, 5833, 6315, 17, 23, 30, 32...


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. Source:Reactome.

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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
AA MetaboliteCHEBI:15843 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
ALAS1 gene:NRF1:PPARGC1BComplexR-HSA-2466384 (Reactome)
ALAS1 gene ProteinENSG00000023330 (ENSEMBL)
ALAS1 geneENSG00000023330 (ENSEMBL)
ALAS1ProteinP13196 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
ATP5B gene:NRF1:PPARGC1BComplexR-HSA-2466375 (Reactome)
ATP5B gene ProteinENSG00000110955 (ENSEMBL)
ATP5B geneENSG00000110955 (ENSEMBL)
ATP5BProteinP06576 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CYCS gene:NRF1:PPARGC1BComplexR-HSA-2466382 (Reactome)
CYCS gene ProteinENSG00000172115 (ENSEMBL)
CYCS geneENSG00000172115 (ENSEMBL)
CYCSProteinP99999 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
ESRRA geneENSG00000173153 (ENSEMBL)
ESRRAProteinP11474 (Uniprot-TrEMBL)
GABPA ProteinQ06546 (Uniprot-TrEMBL)
GABPA geneENSG00000154727 (ENSEMBL)
GABPAProteinQ06546 (Uniprot-TrEMBL)
HCFC1 ProteinP51610 (Uniprot-TrEMBL)
HCFC1ProteinP51610 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
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 geneENSG00000127989 (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.
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 geneENSG00000106459 (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 geneENSG00000107815 (ENSEMBL)
PEO1ProteinQ96RR1 (Uniprot-TrEMBL)
POLG2 geneENSG00000256525 (ENSEMBL)
POLG2(?-485)ProteinQ9UHN1 (Uniprot-TrEMBL)
POLRMTENSG00000099821 (ENSEMBL)
POLRMTProteinO00411 (Uniprot-TrEMBL)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1A gene ProteinENSG00000109189 (ENSEMBL)
PPARGC1A geneENSG00000109189 (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)
RXRA ProteinP19793 (Uniprot-TrEMBL)
SIRT3 geneENSG00000142082 (ENSEMBL)
SIRT3(?-399)ProteinQ9NTG7 (Uniprot-TrEMBL)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
SSBP1 geneENSG00000106028 (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,PPRC1R-HSA-2466363 (Reactome)
TFAM gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466379 (Reactome)
TFAM gene ProteinENSG00000108064 (ENSEMBL)
TFAM geneENSG00000108064 (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,PPRC1R-HSA-2466390 (Reactome)
TFB1M gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466393 (Reactome)
TFB1M gene ProteinENSG00000029639 (ENSEMBL)
TFB1M geneENSG00000029639 (ENSEMBL)
TFB1MProteinQ8WVM0 (Uniprot-TrEMBL)
TFB2M gene:NRF1:NRF2:HCFC1:PPRC1ComplexR-HSA-2466365 (Reactome)
TFB2M gene:NRF1:NRF2:p-PPARGC1A,PPRC1R-HSA-2466378 (Reactome)
TFB2M gene:NRF1:p-PPARGC1A:NRF2ComplexR-HSA-2466376 (Reactome)
TFB2M gene ProteinENSG00000162851 (ENSEMBL)
TFB2M geneENSG00000162851 (ENSEMBL)
TFB2MProteinQ9H5Q4 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
ferriheme b MetaboliteCHEBI:36144 (ChEBI)
p-AMPK heterotrimer:AMPComplexR-HSA-2151198 (Reactome)
p-PPARGC1AR-HSA-1592227 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T178,S539-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T178,S539-PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
p-T263,S266,T299-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T263,S266,T299-PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
phospho-p38

alpha/beta/gamma

MAPK		R-HSA-448858 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
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 gene:NRF1:PPARGC1BR-HSA-1592247 (Reactome)
ATP5B geneR-HSA-2466369 (Reactome)
ATP5BArrowR-HSA-1592247 (Reactome)
ATPR-HSA-1592233 (Reactome)
ATPR-HSA-1592244 (Reactome)
ArrowR-HSA-1368140 (Reactome)
CYCS gene:NRF1:PPARGC1BArrowR-HSA-1592231 (Reactome)
CYCS gene:NRF1:PPARGC1BArrowR-HSA-2466370 (Reactome)
CYCS gene:NRF1:PPARGC1BR-HSA-1592231 (Reactome)
CYCS geneR-HSA-2466370 (Reactome)
CYCSArrowR-HSA-1592231 (Reactome)
ESRRA geneR-HSA-1605428 (Reactome)
ESRRAArrowR-HSA-1592231 (Reactome)
ESRRAArrowR-HSA-1592238 (Reactome)
ESRRAArrowR-HSA-1592247 (Reactome)
ESRRAArrowR-HSA-1605428 (Reactome)
GABPA geneR-HSA-1592234 (Reactome)
GABPAArrowR-HSA-1592234 (Reactome)
GABPAR-HSA-1592240 (Reactome)
HCFC1R-HSA-1592250 (Reactome)
HCFC1R-HSA-2466367 (Reactome)
MTERF geneR-HSA-1592251 (Reactome)
MTERFArrowR-HSA-1592251 (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)
POLG2 geneR-HSA-1592235 (Reactome)
POLG2(?-485)ArrowR-HSA-1592235 (Reactome)
POLRMTArrowR-HSA-1592243 (Reactome)
POLRMTR-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-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).
SIRT3 geneR-HSA-1605535 (Reactome)
SIRT3(?-399)ArrowR-HSA-1605535 (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:NRF2:p-PPARGC1A,PPRC1R-HSA-1592246 (Reactome)
TFAM gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-2466391 (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:NRF2:p-PPARGC1A,PPRC1R-HSA-1592232 (Reactome)
TFB1M gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-1592236 (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:NRF2:p-PPARGC1A,PPRC1R-HSA-1592252 (Reactome)
TFB2M gene:NRF1:p-PPARGC1A:NRF2ArrowR-HSA-2466392 (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-T178,S539-PPARGC1AArrowR-HSA-1592244 (Reactome)
p-T263,S266,T299-PPARGC1AArrowR-HSA-1592233 (Reactome)
p-T69,T71-ATF2ArrowR-HSA-1368140 (Reactome)
phospho-p38

alpha/beta/gamma

MAPK		mim-catalysisR-HSA-1592233 (Reactome)
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