Mitochondrial biogenesis (Homo sapiens)

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6, 8, 10, 19, 20, 24...13, 18, 21, 25, 55...56283, 48, 54, 7953, 57, 814, 38, 6726, 284, 674, 504, 11, 27, 39, 6740, 60, 6923, 67666851, 786523, 30, 47, 50665713, 212828164, 5042, 5923, 674, 67282, 17mitochondrial matrixcytosolmitochondrial intermembrane spacenucleoplasmNRF2 beta-1 subunit TFB1MPERM1NR1D1:heme:Corepressors:PPARGC1A geneRibC-GLUD2 p-T263,S266,T299-PPARGC1A GLUDNRF2 gamma-1 subunit ATP5B gene ALAS1PPARGC1A gene HCFC1GABPA RibC-GLUD1 p-T263,S266,T299-PPARGC1A PPRC1 HCFC1 NRF1 p-S133-CREB1TFAM gene NRF2 beta-2 subunit NRF2 gamma-1 subunit p-T178,S539-PPARGC1AMED1 CREB1SIRT5 NRF2 gamma-1 subunit p-T263,S266,T299-PPARGC1A PRKAG3 TFB2MGABPA NRF2 beta-2 subunit AcK-SOD2 GABPA GABPA NRF2 beta-1 subunit TFB2Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1NRF2 gamma-2 subunit NRF2 gamma-2 subunit p-T178,S539-PPARGC1A POLRMTCa2+ p-T178,S539-PPARGC1A PPARA TFB1M gene PPARGC1B CYCS gene p-T178,S539-PPARGC1A NRF2 beta-2 subunit PPARGC1B SIRT3(?-399) GABPA PPRC1 GLUD2 p-T178,S539-PPARGC1A CYCSGABPA AA NRF1 NRF1 TBL1XR1 NAMSIRT3(?-399)p-PPARGC1ANAMGABPANRF22'-O-acetyl-ADP-riboseMEF2C,D:PPARGC1ANRF2 beta-1 subunit TGS1 ALAS1 geneNRF2 beta-1 subunit TFB2M geneCHD9 p-T178,S539-PPARGC1A Zn2+ ATPMTERF geneNRF2 beta-1 subunit SMARCD3 p-S133-CREB:CRTC1,2,3:PPARGC1A geneNRF2 gamma-1 subunitNRF2 gamma-2 subunitADPESRRANRF2 gamma-2 subunit PPARGC1B ferriheme b p-T178,S539-PPARGC1A PPRC1 CYCSgene:NRF1:PPARGC1Bp-T172-PRKAA2 PRKAB1 SSBP1p-S12,S13-CAMK4 Zn2+ CARM1 TFB1M geneATP5BNRF2 gamma-2 subunit PPARGC1BATP5B geneGABPA TFAMgene:NRF1:p-PPARGC1A:NRF2ACSS2 ATP5Bgene:NRF1:PPARGC1BCristae formationPPRC1EPA NRF1 POLRMT genePeroxisome Proliferator Receptor Element (PPRE) NRF1 NRF1 POLG2 geneLINA TFB1Mgene:NRF1:NRF2:HCFC1:PPRC1TFAM gene Zn2+ PPRC1 RibC-GLUDTFAMALAS1 gene NR1D1 SIRT4 p-T263,S266,T299-PPARGC1A CREBBP p-T180,Y182-MAPK14 MTERFNRF1 NRF2 gamma-1 subunit phospho-CaMKIV:CalmodulinNRF2 gamma-2 subunit SIRT5:Zn2+NRF1 NRF2 beta-1 subunit p-T180,Y182-MAPK11 ESRRA geneNRF2 beta-1 subunit NCOA1 ADPHCFC1 TFB2Mgene:NRF1:NRF2:HCFC1:PPRC1AcK-ACSS2 CRTC3 PPARGC1ATFAM gene HELZ2 CYCS geneCRTC1 TFB1M gene NRF2 gamma-1 subunit GABPA Palm NRF2 beta-1 subunitMitochondrialprotein importp-T263,S266,T299-PPARGC1ANCOR1 p-T178,S539-PPARGC1A NRF1 GABPA TFAMgene:NRF1:NRF2:p-PPARGC1A,PPRC1ATPMAPK12 CALM1 PEO1NRF2 gamma-1 subunit SIRT4:Zn2+HCFC1 p-T69,T71-ATF2NRF1 geneAcK-CYCS2'-O-acetyl-ADP-riboseNRF2 beta-2 subunit NAD+PPARGC1A NCOA2 NRF2 gamma-1 subunit NRF2 gamma-2 subunit NRF2 gamma-2 subunit PPRC1 TFB1Mgene:NRF1:NRF2:p-PPARGC1A,PPRC1SIRT3 genePPARA:RXRACoactivator complexNRF2 gamma-1 subunit TFB1M gene NRF2 gamma-2 subunit phospho-p38alpha/beta/gammaMAPKMEF2D PEO1 genePPARGC1A gene ATPPPARGC1A genep-T263,S266,T299-PPARGC1A GLUD1 PPRC1 NRF2 gamma-2 subunit p-T263,S266,T299-PPARGC1A NRF2 beta-2 subunit TFAM(1-246)NAMNRF1 NRF1 PRKAG1 CRTC2 NAD+SSBP1 geneNRF2 beta-2 subunit PRKAG2 NRF2 gamma-1 subunit Ack-ACCS2,AcK-GLUD,AcK-IDH2,Ack-SOD2ACCS2,GLUD,IDH2,SOD2NRF1NRF2 beta-1 subunit NRF2 beta-1 subunit MEF2C TFB2M gene SIRT3(?-399):Zn2+p-AMPKheterotrimer:AMPNRF2 gamma-2 subunit POLG2(?-485)TFAM genePRKAB2 p-T263,S266,T299-PPARGC1A NCOA6 TBL1X p-S133-CREB1 NRF2 gamma-1 subunit NAD+GABPA TFB2M gene GLUD HCFC1 NRF2 beta-2 subunitAMP HDAC3 RXRA TFB2M gene NRF2 beta-2 subunit PERM1 geneIDH2 NRF1 NRF2 beta-2 subunit ALAS1gene:NRF1:PPARGC1BAcK-IDH2 CYCSNRF2 beta-2 subunit NRF2 beta-1 subunit TFB1Mgene:NRF1:p-PPARGC1A:NRF2TFAMgene:NRF1:NRF2:PPRC1ALA GABPA geneTFB2Mgene:NRF1:p-PPARGC1A:NRF2SOD2 ADPAcK-GLUD NRF2 beta-2 subunit 129664, 23, 47, 50, 6740, 4915, 441, 14, 22, 35, 58...4, 23, 50, 6740, 49470465, 7, 31-33, 41...704615, 4434824, 674, 23, 50, 674, 47, 50, 6712


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.


Pathway is converted from Reactome ID: 1592230
Reactome version: 61
Reactome Author 
Reactome Author: May, Bruce

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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


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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 ProteinP62158 (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-NUL-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)