Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. (Homo sapiens)

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1, 11, 202, 6, 13, 14, 35...22, 26, 32, 36, 46259, 124, 19253616, 3610, 313, 8, 17, 23, 24, 30...3322, 3618, 2722, 364, 2133464, 214, 2122, 36461522, 364, 2122, 3622, 3628, 2922, 364, 2125mitochondrial matrixmitochondrial intermembrane spaceNDUFS4 NDUFS3 NDUFS8 NDUFS2 NDUFB5 NDUFA8 NDUFAF4 MT-ND2MT-ND6 MT-ND3 ATPase:ATPNDUFA2 4Fe-4S NDUFS1 NDUFB9 MT-ATP8 NDUFB11 NDUFAF7 Mitochondrial FattyAcid Beta-OxidationNDUFC2 MT-ND6 NDUFAF3 NDUFS3 ATP5H Fatty Acid "head-in"SDH complex (ox.)NDUFB8 NDUFA8 NDUFA5 NDUFS7 ATP5J ATP5B NDUFS1 ATP5B NDUFA9 COX19NDUFC2 TMEM126B NDUFA3 COQ10A NDUFAF7 FMN Fatty Acid"head-out"4Fe-4S ATP5H ATP5G2 CuA NDUFS7 NDUFB11 NDUFA5 NDUFA6 980kDa complex815kDa complexNDUFA4 MT-ND1ATP5O 4Fe-4S UCP1 NDUFS3 TMEM126B Intermediate 1NDUFB8 F1Fo ATP synthaseETFB 315kDa subcomplexNDUFB10 NDUFA5 NDUFAF44Fe-4S NDUF subunitsH+NDUFAB1 NDUFA2 4Fe-4S NDUFA7 NDUFA6 NDUFA13 NDUFA6 NDUFS1 NDUFB7 NDUFAB1 CoQECSIT ATP5D NDUFS3 NDUFB11 NDUFB5 NDUFB3 MT-ND3NDUFS8 NDUFA11 4Fe-4S NAD+NDUFB10 NDUFAF7FMN NDUFV3 ATP5G2 NDUFS4 NDUFA11 adenosine 5'-monophosphate ATP5G1 NDUFA10 NDUFA1 Iron Sulphur Cluster NDUFA3 NDUFB3 NDUFB3 NDUFS1 NDUFB3 NDUFB9 FADUCP2 NDUFS8 NDUFA3 MT-ND6 NDUFB6 ATP5D ATP5B COX11,14,16,18,20ATP5C1 O2MT-ND4 SDHC NDUFAF5 MT-ND1 NDUFB1 ATPase:ADP:PiNDUFS2 UQCRH ACAD9 NDUFA7 COX18 FAD MT-ND4 NDUFB4 UCP2 Fatty Acid anion "head-in" FAD NDUFB1 NDUFAF4 SLC25A14 NDUFS5MT-ND1 HP subcomplexNDUFS2 FAD NDUFA7 ADPNDUFS8 MT-ND2 LRPPRC COX4I1 NDUFAF7 NDUFAF2 NDUFB6 SLC25A14 NDUFS2 ferroheme NDUFA12CoQ4Fe-4S Fatty Acid anion"head-out"4Fe-4S NDUFAF4 MT-ND3 NDUFAF3 UCP1 COX20 MT-ND1 NDUFB10 NDUFS7 MT-ND4CYCS FAD COX ancilliaryproteinsNDUFB10 TIMMDC1NDUFS4NDUFS2 NDUFAF1 NDUFB4 ETF:FADNDUFAB1 NDUFS8 NDUFS7 CYCS NDUFA12 UCP3 NDUFB9 NDUFS8 NDUFB2 NDUFS6 NDUFA2 4Fe-4S NDUFB1 FAD NDUFB9 NDUFV2:4Fe-4SNDUFC1 NDUFA9 NDUFAF7:NDUFS2:2x4Fe-4SSURF1 TIMMDC1 NDUFA7 NDUFB7 FAD NDUFA12 NDUFA6 MT-ND1 ATP5I NDUFA8 NDUFB2 NDUFC1 ATP5G1 NDUFB4 NDUFA2 Cytochrome c(oxidised)NDUFS1:2x4Fe-4SNDUFB11 FAD ETF:FADH2NDUFB7 Iron Sulphur Cluster NDUFA8 ATP5E 4Fe-4S MT-ND2 ATP5G1 FADH2 NDUFA5 NDUFB2 NDUFA11 NDUFA10 NDUFA10 ferriheme NUBPL:4Fe-4SNDUFC2 NDUFA12 Ubiquinol-cytochromec reductaseNDUFAF3 NDUFA6 CoQNDUFA1 ATP5D 4Fe-4S NDUFA8 COX7C NDUFA2 4Fe-4S MT-ND2 NDUFS2 4Fe-4S UCP dimerNDUFB3 NDUFS7 NDUFV1 NDUFB5 NDUFC1 UCP1 NDUFB4 NDUFC1 H+NDUFB6 COX14 4Fe-4S NDUFS2 370 kDa subcomplexNDUFB3 NDUFS7:4Fe-4SNDUFS8 NDUFA9 COX8A Heme 1 cytochrome c1 cofactor FAD ATP5L COX16 NDUFAF1 NDUFAB1 QH2NDUFA5 TACO1 NDUFB1 NDUFAF5 SDHD MCIA complexNDUFA3 4Fe-4S NDUFB11 NDUFA11 NDUFB7 NDUFB10 H2ONDUFA9 NDUFS8 NDUFS5 H+Complex INDUFB1 FADH2 NDUFA1 NDUFS7 NDUFA1 NDUFAF7 NDUFA5 MT-ATP6 NDUFAF6 L-PheNDUFAF6 NDUFB8 GTP NDUFA13 NDUFS3 ACAD9 NDUFB6 NDUFA1 ATP5L NDUFS3 ATP5O NDUFAF6 NDUFAF7 COX6A1 NDUFA9:FADNDUFB4 550kDa complexNADHCoQNDUFS3MT-ND4 ferriheme H2ONDUFS2 NDUFC1 NDUFA10 MT-ND5 NDUFS7 MT-ND1 4Fe-4S NDUFA8 Fatty Acid anion"head-in"Heme bL NDUFAB1 PM20D14Fe-4S ATP5A1 NDUFAF7 ACAD9 NDUFA8 NDUFA7 NDUFB2 SDHB MT-ATP6 NDUFA6 FAD NDUFS3 NDUFA10 NDUFS2 FP subcomplexFAD ATP5G3 MT-ATP6 NDUFB7 NDUFAF1 NDUFAF3 NDUFA11 NDUFA11 COX11 NDUFA11 ECSIT MT-ND5 COX5A ECSIT NDUFB8 ECSIT ATP5J Fatty Acid anion "head-out" MT-ND6TMEM126B H+NDUF:4Fe-4S subunitsTMEM126B TRAP1MT-ND6 NDUFS7 Cytochrome c oxidaseNDUFV2 CYC1 SCO2 FAD NDUFS3 NDUFAF3 MT-ND2 ATP5C1 MT-ND3 H+ATP5F1 UCP3 4Fe-4S ETFB ATP5F1 COX6C(3-75) TIMMDC1 FAD NDUFB5 MT-ND2 SDHC FAD ATP5F1 UCP1 ATP5A1 NDUFS7 NDUFS6 NDUFA10 SLC25A27 NDUFB9 NDUFAF5 UCP dimerETFA(1-?) NDUFA1 H+NDUFS7 NDUFAF4 NDUFB2 SDHA 4Fe-4SADP NDUFA13 NDUFC2 ATP5S NDUFV3 NDUFA7 QH2NDUFS8 NDUFB5 NDUFS8 FAD NDUFAF6 SCO1 MT-ATP8 FA anion:UCP dimer "head-out" complexNDUFAF2 NDUFB7 NDUFC1 MT-CO2 IP subcomplexH+oleoyl-PheATP5H UQCRFS1(79-274) 4Fe-4S MT-CO3 NDUFAF2UQCRQ TIMMDC1 NDUFV1:4Fe-4S:FMNNDUFS5 FADH2NDUFB8 NDUFB5 MT-ND3 NDUFAB1 ATP5C1 UQCRC2 COX5B SLC25A14 SLC25A27 Heme 2 cytochrome c1 cofactor COX7A2L ATP5S Pi NDUFV1 NDUFV1NDUFA5 ATP5A1 NDUFA9 NDUFB11 NDUFAF1 NDUFB6 NDUFAF7 UCP3 NDUFA2 NDUFA3 SDHB NDUFAF7 NDUFAB1 FA anion:UCP dimer"head-in" complexATP5E NDUFV1 NDUFB5 MT-ND6 SLC25A27 ATP NDUFS8 NDUFV2 NDUFB1 ACAD9 NDUFAF3 adenosine 5'-monophosphate UCP2 H+MT-ND5GDP FMN FMN UCP2 Cytochrome c(reduced)MT-ND5 COQ10B FAD MT-CYB SLC25A27 SDHD ECSIT NDUFV2NDUFV3NDUFAF5NDUFA13 FAD SDHA NDUFS8:2x4Fe-4SUQCR11 NDUFS6 ETFDHNDUFC2 MT-CO1 NDUFB10 NDUFA13 NDUFC2 TIMMDC1 NDUFA1 NUBPLATP5I NDUFB11 NDUFA9 FAD TIMMDC1 NDUFA7 ATP5J2 NDUFB9 Ketone bodymetabolismNDUFV2 ATP5E ATP5J2 NDUFA3 NDUFB6Intermediate 2ATP5L FAD NDUFA13 ETFA(1-?) NDUFA10 NDUFS7 NDUFA13 NDUFB2 TIMMDC1 ATP oleateNDUFA6 MT-ATP8 ATP5J NDUFAF6UQCR10 ATP5J2 NDUFS1 Purine nucleotideQH24Fe-4S NDUFA2 Succinatedehydrogenasecomplex (reduced)MT-ND3 Pi2Fe-2S ATP5G3 ACAD9 NDUFV3 NDUFC1 NDUFA9 NDUFB9 Cytochrome c(oxidised)NDUFAF4 UCP3 NUBPL ATPH2OSLC25A14 NDUFAF5 NDUFB1 NDUFB2 NDUFB4 ATP5G2 COQ10A,BCOX7B FMNTMEM126B NDUFAF4 ADP NDUFC2 NDUFAF3NDUFAF1 LCFAH+NDUFB3 NDUFB4 NDUFS6ATP5G3 ATP5S UQCRB NDUFA3 NDUFA9 NDUFB8 NDUFB8 COX6B1 NDUFB10 NDUFB7 UQCRC1 NDUFA9 ATP5I NDUFS1 NDUFS2 ATP5O CYCS NDUFS2 NDUFS4 NDUFV1 NDUFV2 5, 437, 39, 40, 4544


Description

Oxidation of fatty acids and pyruvate in the mitochondrial matrix yield large amounts of NADH. The respiratory electron transport chain couples the re-oxidation of this NADH to NAD+ to the export of protons from the mitochonrial matrix, generating a chemiosmotic gradient across the inner mitochondrial membrane. This gradient is used to drive the synthesis of ATP; it can also be bypassed by uncoupling proteins to generate heat, a reaction in brown fat that may be important in regulation of body temperature in newborn children. View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 163200
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114966view16:49, 25 January 2021ReactomeTeamReactome version 75
113410view11:48, 2 November 2020ReactomeTeamReactome version 74
112612view15:59, 9 October 2020ReactomeTeamReactome version 73
101528view11:39, 1 November 2018ReactomeTeamreactome version 66
101063view21:21, 31 October 2018ReactomeTeamreactome version 65
100594view19:55, 31 October 2018ReactomeTeamreactome version 64
100143view16:40, 31 October 2018ReactomeTeamreactome version 63
99693view15:09, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99281view12:45, 31 October 2018ReactomeTeamreactome version 62
93907view13:44, 16 August 2017ReactomeTeamreactome version 61
93481view11:24, 9 August 2017ReactomeTeamreactome version 61
86578view09:21, 11 July 2016ReactomeTeamreactome version 56
83426view11:11, 18 November 2015ReactomeTeamVersion54
81630view13:10, 21 August 2015ReactomeTeamVersion53
77091view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76797view12:18, 16 July 2014ReactomeTeamFixed remaining interactions
76120view10:18, 11 June 2014ReactomeTeamRe-fixing comment source
75832view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75192view09:40, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74837view10:06, 30 April 2014ReactomeTeamReactome46
74431view07:10, 19 April 2014EgonwRelocated an InfoBox.
68937view17:34, 8 July 2013MaintBotUpdated to 2013 gpml schema
45047view19:09, 6 October 2011ThomasOntology Term : 'energy metabolic pathway' added !
42118view21:58, 4 March 2011MaintBotAutomatic update
39928view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2Fe-2S R-ALL-164296 (Reactome)
315kDa subcomplexComplexR-HSA-6799189 (Reactome)
370 kDa subcomplexComplexR-HSA-6799190 (Reactome)
4Fe-4S R-ALL-164292 (Reactome)
4Fe-4S R-ALL-169274 (Reactome)
4Fe-4SR-ALL-169274 (Reactome)
550kDa complexComplexR-HSA-6799176 (Reactome)
815kDa complexComplexR-HSA-6799187 (Reactome)
980kDa complexComplexR-HSA-6799183 (Reactome)
ACAD9 ProteinQ9H845 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:456216 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATP MetaboliteCHEBI:30616 (ChEBI)
ATP5A1 ProteinP25705 (Uniprot-TrEMBL)
ATP5B ProteinP06576 (Uniprot-TrEMBL)
ATP5C1 ProteinP36542 (Uniprot-TrEMBL)
ATP5D ProteinP30049 (Uniprot-TrEMBL)
ATP5E ProteinP56381 (Uniprot-TrEMBL)
ATP5F1 ProteinP24539 (Uniprot-TrEMBL)
ATP5G1 ProteinP05496 (Uniprot-TrEMBL)
ATP5G2 ProteinQ06055 (Uniprot-TrEMBL)
ATP5G3 ProteinP48201 (Uniprot-TrEMBL)
ATP5H ProteinO75947 (Uniprot-TrEMBL)
ATP5I ProteinP56385 (Uniprot-TrEMBL)
ATP5J ProteinP18859 (Uniprot-TrEMBL)
ATP5J2 ProteinP56134 (Uniprot-TrEMBL)
ATP5L ProteinO75964 (Uniprot-TrEMBL)
ATP5O ProteinP48047 (Uniprot-TrEMBL)
ATP5S ProteinQ99766 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
ATPase:ADP:PiComplexR-HSA-164838 (Reactome)
ATPase:ATPComplexR-HSA-164835 (Reactome)
COQ10A ProteinQ96MF6 (Uniprot-TrEMBL)
COQ10A,BComplexR-HSA-8933103 (Reactome)
COQ10B ProteinQ9H8M1 (Uniprot-TrEMBL)
COX ancilliary proteinsComplexR-HSA-5566488 (Reactome)
COX11 ProteinQ9Y6N1 (Uniprot-TrEMBL)
COX11,14,16,18,20ComplexR-HSA-5336143 (Reactome)
COX14 ProteinQ96I36 (Uniprot-TrEMBL)
COX16 ProteinQ9P0S2 (Uniprot-TrEMBL)
COX18 ProteinQ8N8Q8 (Uniprot-TrEMBL)
COX19ProteinQ3E731 (Uniprot-TrEMBL)
COX20 ProteinQ5RI15 (Uniprot-TrEMBL)
COX4I1 ProteinP13073 (Uniprot-TrEMBL)
COX5A ProteinP20674 (Uniprot-TrEMBL)
COX5B ProteinP10606 (Uniprot-TrEMBL)
COX6A1 ProteinP12074 (Uniprot-TrEMBL)
COX6B1 ProteinP14854 (Uniprot-TrEMBL)
COX6C(3-75) ProteinP09669 (Uniprot-TrEMBL)
COX7A2L ProteinO14548 (Uniprot-TrEMBL)
COX7B ProteinP24311 (Uniprot-TrEMBL)
COX7C ProteinP15954 (Uniprot-TrEMBL)
COX8A ProteinP10176 (Uniprot-TrEMBL)
CYC1 ProteinP08574 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
CoQMetaboliteCHEBI:46245 (ChEBI)
Complex IComplexR-HSA-6799192 (Reactome)
CuA MetaboliteCHEBI:28694 (ChEBI)
Cytochrome c (oxidised)ComplexR-HSA-352607 (Reactome)
Cytochrome c (reduced)ComplexR-HSA-352609 (Reactome)
Cytochrome c oxidaseComplexR-HSA-164316 (Reactome)
ECSIT ProteinQ9BQ95 (Uniprot-TrEMBL)
ETF:FADH2ComplexR-HSA-169268 (Reactome)
ETF:FADComplexR-HSA-169267 (Reactome)
ETFA(1-?) ProteinP13804 (Uniprot-TrEMBL)
ETFB ProteinP38117 (Uniprot-TrEMBL)
ETFDHProteinQ16134 (Uniprot-TrEMBL)
F1Fo ATP synthaseComplexR-HSA-74186 (Reactome) Mitochondrial ATP synthase subunit s (ATP5S) appears to be an essential subunit necessary for H+ conduction of ATP synthase (Belogrudov & Hatefi 2002, Belogrudov 2002).
FA anion:UCP dimer "head-in" complexComplexR-HSA-166218 (Reactome)
FA anion:UCP dimer "head-out" complexComplexR-HSA-166385 (Reactome)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADMetaboliteCHEBI:16238 (ChEBI)
FADH2 MetaboliteCHEBI:17877 (ChEBI)
FADH2MetaboliteCHEBI:17877 (ChEBI)
FMN MetaboliteCHEBI:17621 (ChEBI)
FMNMetaboliteCHEBI:17621 (ChEBI)
FP subcomplexComplexR-HSA-5689686 (Reactome)
Fatty Acid "head-out"MetaboliteCHEBI:35366 (ChEBI)
Fatty Acid "head-in"MetaboliteCHEBI:35366 (ChEBI)
Fatty Acid anion "head-in"MetaboliteCHEBI:28868 (ChEBI)
Fatty Acid anion "head-out"MetaboliteCHEBI:28868 (ChEBI)
Fatty Acid anion "head-in" MetaboliteCHEBI:28868 (ChEBI)
Fatty Acid anion "head-out" MetaboliteCHEBI:28868 (ChEBI)
GDP MetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HP subcomplexComplexR-HSA-163929 (Reactome)
Heme 1 cytochrome c1 cofactor R-ALL-164585 (Reactome)
Heme 2 cytochrome c1 cofactor R-ALL-164586 (Reactome)
Heme bL R-ALL-164657 (Reactome)
IP subcomplexComplexR-HSA-5689699 (Reactome)
Intermediate 1ComplexR-HSA-6788529 (Reactome)
Intermediate 2ComplexR-HSA-6799181 (Reactome)
Iron Sulphur Cluster R-ALL-113591 (Reactome)
Ketone body metabolismPathwayR-HSA-74182 (Reactome) Acetoacetate, beta-hydroxybutyrate, and acetone collectively are called ketone bodies. The first two are synthesized from acetyl-CoA, in the mitochondria of liver cells; acetone is formed by spontaneous decarboxylation of acetoacetate. Ketone body synthesis in liver is effectively irreversible because the enzyme that catalyzes the conversion of acetoacetate to acetoacetyl-CoA is not present in liver cells.

Ketone bodies, unlike fatty acids and triglycerides, are water-soluble. They are exported from the liver, and are taken up by other tissues, notably brain and skeletal and cardiac muscle. There, they are broken down to acetyl-CoA which is oxidized via the TCA cycle to yield energy. In a normal person, this pathway of ketone body synthesis and utilization is most active during extended periods of fasting. Under these conditions, mobilization and breakdown of stored fatty acids generates abundant acetyl-CoA acetyl-CoA in liver cells for synthesis of ketone bodies, and their utilization in other tissues minimizes the demand of these tissues for glucose (Sass 2011).

L-PheMetaboliteCHEBI:58095 (ChEBI)
LCFAMetaboliteCHEBI:15904 (ChEBI)
LRPPRC ProteinP42704 (Uniprot-TrEMBL)
MCIA complexComplexR-HSA-5689052 (Reactome)
MT-ATP6 ProteinP00846 (Uniprot-TrEMBL)
MT-ATP8 ProteinP03928 (Uniprot-TrEMBL)
MT-CO1 ProteinP00395 (Uniprot-TrEMBL)
MT-CO2 ProteinP00403 (Uniprot-TrEMBL)
MT-CO3 ProteinP00414 (Uniprot-TrEMBL)
MT-CYB ProteinP00156 (Uniprot-TrEMBL)
MT-ND1 ProteinP03886 (Uniprot-TrEMBL)
MT-ND1ProteinP03886 (Uniprot-TrEMBL)
MT-ND2 ProteinP03891 (Uniprot-TrEMBL)
MT-ND2ProteinP03891 (Uniprot-TrEMBL)
MT-ND3 ProteinP03897 (Uniprot-TrEMBL)
MT-ND3ProteinP03897 (Uniprot-TrEMBL)
MT-ND4 ProteinP03905 (Uniprot-TrEMBL)
MT-ND4ProteinP03905 (Uniprot-TrEMBL)
MT-ND5 ProteinP03915 (Uniprot-TrEMBL)
MT-ND5ProteinP03915 (Uniprot-TrEMBL)
MT-ND6 ProteinP03923 (Uniprot-TrEMBL)
MT-ND6ProteinP03923 (Uniprot-TrEMBL)
Mitochondrial Fatty Acid Beta-OxidationPathwayR-HSA-77289 (Reactome) Beta-oxidation begins once fatty acids have been imported into the mitochondrial matrix by carnitine acyltransferases. The beta-oxidation spiral of fatty acids metabolism involves the repetitive removal of two carbon units from the fatty acyl chain. There are four steps to this process: oxidation, hydration, a second oxidation, and finally thiolysis. The last step releases the two-carbon acetyl-CoA and a ready primed acyl-CoA that takes another turn down the spiral. In total each turn of the beta-oxidation spiral produces one NADH, one FADH2, and one acetyl-CoA.

Further oxidation of acetyl-CoA via the tricarboxylic acid cycle generates additional FADH2 and NADH. All reduced cofactors are used by the mitochondrial electron transport chain to form ATP. The complete oxidation of a fatty acid molecule produces numerous ATP molecules. Palmitate, used as the model here, produces 129 ATPs.

Beta-oxidation pathways differ for saturated and unsaturated fatty acids. The beta-oxidation of saturated fatty acids requires four different enzymatic steps. Beta-oxidation produces and consumes intermediates with a trans configuration; unsaturated fatty acids that have bonds in the cis configuration require three separate enzymatic steps to prepare these molecules for the beta-oxidation pathway.

NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NDUF subunitsComplexR-HSA-6788518 (Reactome)
NDUF:4Fe-4S subunitsComplexR-HSA-6788527 (Reactome)
NDUFA1 ProteinO15239 (Uniprot-TrEMBL)
NDUFA10 ProteinO95299 (Uniprot-TrEMBL)
NDUFA11 ProteinQ86Y39 (Uniprot-TrEMBL)
NDUFA12 ProteinQ9UI09 (Uniprot-TrEMBL)
NDUFA12ProteinQ9UI09 (Uniprot-TrEMBL)
NDUFA13 ProteinQ9P0J0 (Uniprot-TrEMBL)
NDUFA2 ProteinO43678 (Uniprot-TrEMBL)
NDUFA3 ProteinO95167 (Uniprot-TrEMBL)
NDUFA4 ProteinO00483 (Uniprot-TrEMBL)
NDUFA5 ProteinQ16718 (Uniprot-TrEMBL)
NDUFA6 ProteinP56556 (Uniprot-TrEMBL)
NDUFA7 ProteinO95182 (Uniprot-TrEMBL)
NDUFA8 ProteinP51970 (Uniprot-TrEMBL)
NDUFA9 ProteinQ16795 (Uniprot-TrEMBL)
NDUFA9:FADComplexR-HSA-164289 (Reactome)
NDUFAB1 ProteinO14561 (Uniprot-TrEMBL)
NDUFAF1 ProteinQ9Y375 (Uniprot-TrEMBL)
NDUFAF2 ProteinQ8N183 (Uniprot-TrEMBL)
NDUFAF2ProteinQ8N183 (Uniprot-TrEMBL)
NDUFAF3 ProteinQ9BU61 (Uniprot-TrEMBL)
NDUFAF3ProteinQ9BU61 (Uniprot-TrEMBL)
NDUFAF4 ProteinQ9P032 (Uniprot-TrEMBL)
NDUFAF4ProteinQ9P032 (Uniprot-TrEMBL)
NDUFAF5 ProteinQ5TEU4 (Uniprot-TrEMBL)
NDUFAF5ProteinQ5TEU4 (Uniprot-TrEMBL)
NDUFAF6 ProteinQ330K2 (Uniprot-TrEMBL)
NDUFAF6ProteinQ330K2 (Uniprot-TrEMBL)
NDUFAF7 ProteinQ7L592 (Uniprot-TrEMBL)
NDUFAF7:NDUFS2:2x4Fe-4SComplexR-HSA-164288 (Reactome)
NDUFAF7ProteinQ7L592 (Uniprot-TrEMBL)
NDUFB1 ProteinO75438 (Uniprot-TrEMBL)
NDUFB10 ProteinO96000 (Uniprot-TrEMBL)
NDUFB11 ProteinQ9NX14 (Uniprot-TrEMBL)
NDUFB2 ProteinO95178 (Uniprot-TrEMBL)
NDUFB3 ProteinO43676 (Uniprot-TrEMBL)
NDUFB4 ProteinO95168 (Uniprot-TrEMBL)
NDUFB5 ProteinO43674 (Uniprot-TrEMBL)
NDUFB6 ProteinO95139 (Uniprot-TrEMBL)
NDUFB6ProteinO95139 (Uniprot-TrEMBL)
NDUFB7 ProteinP17568 (Uniprot-TrEMBL)
NDUFB8 ProteinO95169 (Uniprot-TrEMBL)
NDUFB9 ProteinQ9Y6M9 (Uniprot-TrEMBL)
NDUFC1 ProteinO43677 (Uniprot-TrEMBL)
NDUFC2 ProteinO95298 (Uniprot-TrEMBL)
NDUFS1 ProteinP28331 (Uniprot-TrEMBL)
NDUFS1:2x4Fe-4SComplexR-HSA-164297 (Reactome)
NDUFS2 ProteinO75306 (Uniprot-TrEMBL)
NDUFS3 ProteinO75489 (Uniprot-TrEMBL)
NDUFS3ProteinO75489 (Uniprot-TrEMBL)
NDUFS4 ProteinO43181 (Uniprot-TrEMBL)
NDUFS4ProteinO43181 (Uniprot-TrEMBL)
NDUFS5 ProteinO43920 (Uniprot-TrEMBL)
NDUFS5ProteinO43920 (Uniprot-TrEMBL)
NDUFS6 ProteinO75380 (Uniprot-TrEMBL)
NDUFS6ProteinO75380 (Uniprot-TrEMBL)
NDUFS7 ProteinO75251 (Uniprot-TrEMBL)
NDUFS7:4Fe-4SComplexR-HSA-164293 (Reactome)
NDUFS8 ProteinO00217 (Uniprot-TrEMBL)
NDUFS8:2x4Fe-4SComplexR-HSA-164295 (Reactome)
NDUFV1 ProteinP49821 (Uniprot-TrEMBL)
NDUFV1:4Fe-4S:FMNComplexR-HSA-6788516 (Reactome)
NDUFV1ProteinP49821 (Uniprot-TrEMBL)
NDUFV2 ProteinP19404 (Uniprot-TrEMBL)
NDUFV2:4Fe-4SComplexR-HSA-6788524 (Reactome)
NDUFV2ProteinP19404 (Uniprot-TrEMBL)
NDUFV3 ProteinP56181 (Uniprot-TrEMBL)
NDUFV3ProteinP56181 (Uniprot-TrEMBL)
NUBPL ProteinQ8TB37 (Uniprot-TrEMBL)
NUBPL:4Fe-4SComplexR-HSA-5690007 (Reactome)
NUBPLProteinQ8TB37 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PM20D1ProteinQ6GTS8 (Uniprot-TrEMBL)
Pi MetaboliteCHEBI:18367 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
Purine nucleotideComplexR-ALL-170037 (Reactome)
QH2MetaboliteCHEBI:17976 (ChEBI)
SCO1 ProteinO75880 (Uniprot-TrEMBL)
SCO2 ProteinO43819 (Uniprot-TrEMBL)
SDH complex (ox.)ComplexR-HSA-70990 (Reactome)
SDHA ProteinP31040 (Uniprot-TrEMBL)
SDHB ProteinP21912 (Uniprot-TrEMBL)
SDHC ProteinQ99643 (Uniprot-TrEMBL)
SDHD ProteinO14521 (Uniprot-TrEMBL)
SLC25A14 ProteinO95258 (Uniprot-TrEMBL)
SLC25A27 ProteinO95847 (Uniprot-TrEMBL)
SURF1 ProteinQ15526 (Uniprot-TrEMBL)
Succinate

dehydrogenase

complex (reduced)
ComplexR-HSA-165631 (Reactome)
TACO1 ProteinQ9BSH4 (Uniprot-TrEMBL)
TIMMDC1 ProteinQ9NPL8 (Uniprot-TrEMBL)
TIMMDC1ProteinQ9NPL8 (Uniprot-TrEMBL)
TMEM126B ProteinQ8IUX1 (Uniprot-TrEMBL)
TRAP1ProteinQ12931 (Uniprot-TrEMBL)
UCP dimerComplexR-HSA-166389 (Reactome)
UCP1 ProteinP25874 (Uniprot-TrEMBL)
UCP2 ProteinP55851 (Uniprot-TrEMBL)
UCP3 ProteinP55916 (Uniprot-TrEMBL)
UQCR10 ProteinQ9UDW1 (Uniprot-TrEMBL)
UQCR11 ProteinO14957 (Uniprot-TrEMBL)
UQCRB ProteinP14927 (Uniprot-TrEMBL)
UQCRC1 ProteinP31930 (Uniprot-TrEMBL)
UQCRC2 ProteinP22695 (Uniprot-TrEMBL)
UQCRFS1(79-274) ProteinP47985 (Uniprot-TrEMBL)
UQCRH ProteinP07919 (Uniprot-TrEMBL)
UQCRQ ProteinO14949 (Uniprot-TrEMBL)
Ubiquinol-cytochrome c reductaseComplexR-HSA-164317 (Reactome)
adenosine 5'-monophosphate MetaboliteCHEBI:16027 (ChEBI)
ferriheme MetaboliteCHEBI:38574 (ChEBI)
ferroheme MetaboliteCHEBI:38573 (ChEBI)
oleateMetaboliteCHEBI:30823 (ChEBI)
oleoyl-PheMetaboliteCHEBI:134020 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
315kDa subcomplexArrowR-HSA-6799191 (Reactome)
315kDa subcomplexR-HSA-6799202 (Reactome)
370 kDa subcomplexArrowR-HSA-6799199 (Reactome)
370 kDa subcomplexR-HSA-6799202 (Reactome)
4Fe-4SR-HSA-5690023 (Reactome)
550kDa complexArrowR-HSA-6799202 (Reactome)
550kDa complexR-HSA-6799197 (Reactome)
815kDa complexArrowR-HSA-6799197 (Reactome)
815kDa complexR-HSA-6799179 (Reactome)
980kDa complexArrowR-HSA-6799179 (Reactome)
980kDa complexR-HSA-6799196 (Reactome)
ADPR-HSA-164840 (Reactome)
ATPArrowR-HSA-164834 (Reactome)
ATPase:ADP:PiArrowR-HSA-164840 (Reactome)
ATPase:ADP:PiR-HSA-164832 (Reactome)
ATPase:ADP:Pimim-catalysisR-HSA-164832 (Reactome)
ATPase:ATPArrowR-HSA-164832 (Reactome)
ATPase:ATPR-HSA-164834 (Reactome)
ATPase:ATPmim-catalysisR-HSA-164834 (Reactome)
COQ10A,BArrowR-HSA-163217 (Reactome)
COX ancilliary proteinsArrowR-HSA-163214 (Reactome)
COX11,14,16,18,20ArrowR-HSA-163214 (Reactome)
COX19ArrowR-HSA-163214 (Reactome)
CoQArrowR-HSA-164651 (Reactome)
CoQR-HSA-163213 (Reactome)
CoQR-HSA-163217 (Reactome)
CoQR-HSA-164651 (Reactome)
CoQR-HSA-169270 (Reactome)
Complex IArrowR-HSA-6799196 (Reactome)
Complex Imim-catalysisR-HSA-163217 (Reactome)
Cytochrome c (oxidised)ArrowR-HSA-163214 (Reactome)
Cytochrome c (oxidised)R-HSA-164651 (Reactome)
Cytochrome c (reduced)ArrowR-HSA-164651 (Reactome)
Cytochrome c (reduced)R-HSA-163214 (Reactome)
Cytochrome c oxidasemim-catalysisR-HSA-163214 (Reactome)
ETF:FADArrowR-HSA-169270 (Reactome)
ETF:FADH2ArrowR-HSA-169260 (Reactome)
ETF:FADH2R-HSA-169270 (Reactome)
ETF:FADR-HSA-169260 (Reactome)
ETF:FADmim-catalysisR-HSA-169260 (Reactome)
ETFDHmim-catalysisR-HSA-169270 (Reactome)
F1Fo ATP synthaseArrowR-HSA-164834 (Reactome)
F1Fo ATP synthaseR-HSA-164840 (Reactome)
FA anion:UCP dimer "head-in" complexArrowR-HSA-166220 (Reactome)
FA anion:UCP dimer "head-in" complexR-HSA-166214 (Reactome)
FA anion:UCP dimer "head-in" complexmim-catalysisR-HSA-166214 (Reactome)
FA anion:UCP dimer "head-out" complexArrowR-HSA-166214 (Reactome)
FA anion:UCP dimer "head-out" complexR-HSA-166387 (Reactome)
FADArrowR-HSA-169260 (Reactome)
FADH2R-HSA-169260 (Reactome)
FMNR-HSA-6788556 (Reactome)
FP subcomplexArrowR-HSA-6800870 (Reactome)
FP subcomplexR-HSA-6799179 (Reactome)
Fatty Acid "head-out"ArrowR-HSA-166219 (Reactome)
Fatty Acid "head-out"R-HSA-166215 (Reactome)
Fatty Acid "head-in"ArrowR-HSA-166215 (Reactome)
Fatty Acid "head-in"R-HSA-166223 (Reactome)
Fatty Acid anion "head-in"ArrowR-HSA-166223 (Reactome)
Fatty Acid anion "head-in"R-HSA-166220 (Reactome)
Fatty Acid anion "head-out"ArrowR-HSA-166387 (Reactome)
Fatty Acid anion "head-out"R-HSA-166219 (Reactome)
H+ArrowR-HSA-163214 (Reactome)
H+ArrowR-HSA-163217 (Reactome)
H+ArrowR-HSA-164651 (Reactome)
H+ArrowR-HSA-164834 (Reactome)
H+ArrowR-HSA-166223 (Reactome)
H+ArrowR-HSA-170026 (Reactome)
H+R-HSA-163214 (Reactome)
H+R-HSA-163217 (Reactome)
H+R-HSA-164651 (Reactome)
H+R-HSA-164834 (Reactome)
H+R-HSA-166219 (Reactome)
H+R-HSA-170026 (Reactome)
H2OArrowR-HSA-163214 (Reactome)
H2OArrowR-HSA-164832 (Reactome)
H2OArrowR-HSA-9673053 (Reactome)
H2OR-HSA-9673054 (Reactome)
HP subcomplexR-HSA-6799178 (Reactome)
IP subcomplexArrowR-HSA-6800868 (Reactome)
IP subcomplexR-HSA-6799203 (Reactome)
Intermediate 1ArrowR-HSA-6799203 (Reactome)
Intermediate 1R-HSA-6799178 (Reactome)
Intermediate 2ArrowR-HSA-6799178 (Reactome)
Intermediate 2R-HSA-6799191 (Reactome)
L-PheArrowR-HSA-9673054 (Reactome)
L-PheR-HSA-9673053 (Reactome)
LCFAArrowR-HSA-170026 (Reactome)
MCIA complexArrowR-HSA-6799196 (Reactome)
MCIA complexR-HSA-6799199 (Reactome)
MT-ND1R-HSA-6799191 (Reactome)
MT-ND2R-HSA-6799199 (Reactome)
MT-ND3R-HSA-6799199 (Reactome)
MT-ND4R-HSA-6799197 (Reactome)
MT-ND5R-HSA-6799197 (Reactome)
MT-ND6R-HSA-6799199 (Reactome)
NAD+ArrowR-HSA-163217 (Reactome)
NADHR-HSA-163217 (Reactome)
NDUF subunitsR-HSA-6788523 (Reactome)
NDUF:4Fe-4S subunitsArrowR-HSA-6788523 (Reactome)
NDUFA12R-HSA-6800870 (Reactome)
NDUFA9:FADR-HSA-6800868 (Reactome)
NDUFAF2ArrowR-HSA-6799196 (Reactome)
NDUFAF2R-HSA-6800870 (Reactome)
NDUFAF3ArrowR-HSA-6799196 (Reactome)
NDUFAF3R-HSA-6799203 (Reactome)
NDUFAF4ArrowR-HSA-6799196 (Reactome)
NDUFAF4R-HSA-6799203 (Reactome)
NDUFAF5ArrowR-HSA-6799196 (Reactome)
NDUFAF5R-HSA-6799191 (Reactome)
NDUFAF6ArrowR-HSA-6799196 (Reactome)
NDUFAF6R-HSA-6799191 (Reactome)
NDUFAF7:NDUFS2:2x4Fe-4SR-HSA-6800868 (Reactome)
NDUFAF7ArrowR-HSA-6799196 (Reactome)
NDUFB6R-HSA-6799199 (Reactome)
NDUFS1:2x4Fe-4SR-HSA-6800870 (Reactome)
NDUFS3R-HSA-6800868 (Reactome)
NDUFS4R-HSA-6800870 (Reactome)
NDUFS5R-HSA-6799179 (Reactome)
NDUFS6R-HSA-6800870 (Reactome)
NDUFS7:4Fe-4SR-HSA-6800868 (Reactome)
NDUFS8:2x4Fe-4SR-HSA-6800868 (Reactome)
NDUFV1:4Fe-4S:FMNArrowR-HSA-6788556 (Reactome)
NDUFV1:4Fe-4S:FMNR-HSA-6800870 (Reactome)
NDUFV1R-HSA-6788556 (Reactome)
NDUFV2:4Fe-4SArrowR-HSA-6788556 (Reactome)
NDUFV2:4Fe-4SR-HSA-6800870 (Reactome)
NDUFV2R-HSA-6788556 (Reactome)
NDUFV3R-HSA-6800870 (Reactome)
NUBPL:4Fe-4SArrowR-HSA-5690023 (Reactome)
NUBPL:4Fe-4SR-HSA-6788523 (Reactome)
NUBPL:4Fe-4SR-HSA-6788556 (Reactome)
NUBPLArrowR-HSA-6788523 (Reactome)
NUBPLArrowR-HSA-6788556 (Reactome)
NUBPLR-HSA-5690023 (Reactome)
O2R-HSA-163214 (Reactome)
PM20D1mim-catalysisR-HSA-9673053 (Reactome)
PM20D1mim-catalysisR-HSA-9673054 (Reactome)
PiR-HSA-164840 (Reactome)
Purine nucleotideTBarR-HSA-170026 (Reactome)
QH2ArrowR-HSA-163213 (Reactome)
QH2ArrowR-HSA-163217 (Reactome)
QH2ArrowR-HSA-164651 (Reactome)
QH2ArrowR-HSA-169270 (Reactome)
QH2R-HSA-164651 (Reactome)
R-HSA-163213 (Reactome) This event is deduced on the basis of bovine experimental data.
Complex II (succinate dehydrogenase) transfers electrons from the TCA cycle to ubiquinone. The 6th step in the TCA cycle is where succinate is dehydrogenated to fumarate with subsequent reduction of FAD to FADH2. FADH2 provides the electrons for the transport chain. Succinate dehydrogenase belongs to subclass 1 of the SQR family (succinate:quinone reductase) (classified by Hagerhall, C and Hederstedt, L [1996]).
It consists of 4 subunits (referred to as A, B, C and D), all nuclear-encoded and is located on the matrix side of the inner mitochondrial membrane. Subunits A and B are hydrophilic whereas subunits C and D are integral proteins of the inner membrane. SQRs usually contain 3 Fe-S clusters bound by the B subunit. Succinate dehydrogenase contains one [2Fe-2S] cluster, one [4Fe-4S] cluster and one [3Fe-4S] cluster. Additionally, the A subunit has a covalently-bound FAD group. Reduced complex II has this FAD converted to FADH2. The electrons from complex II are transferred to ubiquinone (also called Q, Coenzyme Q or CoQ), a small mobile carrier of electrons located within the inner membrane. Ubiquinone is reduced to ubiquinol during this process.

The mitochondrial heat shock protein 75 kDa (TRAP1) inhibits Complex II of the respiratory chain which elicits respiratory downregulation, leading to a pseudohypoxic state. This state is caused by succinate-dependent HIF1-alpha stabilisation which, in turn, can promote tumorigenesis (Sciacovelli et al. 2013, Yoshida et al. 2013, Guzzo et al. 2014).
R-HSA-163214 (Reactome) Complex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as

4Cyt c (red.) + 12H+ (in) + O2 = 4Cyt c (ox.) + 2H2O + 8H+ (out)

Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space.

COX ancillary proteins mediate membrane insertion, catalytic core processing, copper transport and insertion into core subunits and heme A biosynthesis (Stilburek et al. 2006, Fontanesi et al. 2006, Soto et al. 2012). To date, all Mendelian disorders presenting COX deficiency have been assigned to mutations in ancillary factors, with the exception of an infantile encephalomyopathy caused by a defective COX6B1 and an exocrine pancreatic insufficiency caused by a defective COX4I2 gene (Soto et al. 2012). Balsa et al have shown that NDUFA4, formerly considered to be a constituent of NADH dehydrogenase (Complex I), is instead a component of the cytochrome c oxidase (CIV) (Balsa et al. 2012). Patients with NDUFA4 mutations display COX deficiencies (Pitceathly et al. 2013).
R-HSA-163217 (Reactome) Complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) utilizes NADH formed from glycolysis and the TCA cycle to pump protons out of the mitochondrial matrix. It is the largest enzyme complex in the electron transport chain, containing 45 subunits. Seven subunits (ND1-6, ND4L) are encoded by mitochondrial DNA (Loeffen et al [1998]), the remainder are encoded in the nucleus. The enzyme has a FMN prosthetic group and 8 Iron-Sulfur (Fe-S) clusters. The electrons from NADH oxidation pass through the flavin (FMN) and Fe-S clusters to ubiquinone (CoQ). This electron transfer is coupled with the translocation of protons from the mitochondrial matrix to the intermembrane space. For each electron transferred, 2 protons can be pumped out of the matrix. As there are 2 electrons transferred, 4 protons can be pumped out.
Complex I is made up of 3 sub-complexes - Iron-Sulfur protein fraction (IP), Flavoprotein fraction (FP) and the Hydrophobic protein fraction (HP), probably arranged in an L-shaped structure with the IP and FP fractions protruding into the mitochondrial matrix and the HP arm lying within the inner mitochondrial membrane. The overall reaction can be summed as below:
NADH + Ubiquinone + 5H+ (mito. matrix) = NAD+ + Ubiquinol + 4H+ (intermemb. space)
The electrons from complex I are transferred to ubiquinone (Coenzyme Q, CoQ), a small mobile carrier of electrons located within the inner membrane. Ubiquinone is reduced to ubiquinol (QH2) during this process.

Mitochondrial coenzyme Q-binding protein COQ10 homologs A and B (COQ10A and B) are thought to be required for correct coenzyme CoQ in the respiratory chain. Their function in humans is unknown but the yeast model suggests functions in facilitating de novo CoQ biosynthesis and in delivering it to one or more complexes of the respiratory electron transport chain (Barros et al. 2005, Allan et al. 2013).
R-HSA-164651 (Reactome) The protonmotive Q cycle is the mechanism by which complex III transfers electrons from ubiquinol to cytochrome c, linking this process to translocation of protons across the membrane. This cycle is complicated by the fact that both ubiquinol is oxidised and ubiquinone is reduced during this process. Through a complex series of electron transfers, Complex III consumes two molecules of ubiquinol (QH2) and two molecules of oxidized cytochrome c, generates one molecule of ubiquinone (Q) and two molecules of reduced cytochrome c, regenerates one molecule of ubiquinol (QH2), and mediates the translocation of two protons from the mitochondrial matrix to the mitochondrial intermembrane space. The overall reaction can be summed up as

2QH2 + 2cyt c (ox.) + Q + 2H+ (matrix) = 2Q + 2cyt c (red.) + QH2 + 4H+ (intermemb. space)
R-HSA-164832 (Reactome) In the tight configuration, the beta subunit catalyzes the reaction of ADP + Pi to ATP + water. ATP is still tightly bound to the subunit at this stage.
R-HSA-164834 (Reactome) In the last step, the beta subunit is converted to the open form and ATP is released. Passage of protons through the Fo part causes a ring of approximately 10 subunits to rotate. This rotation in turn drives the rotation of the gamma subunits, which forms part of one of the stalks. The gamma subunit moves between the three beta subunits which are held in place by the second stalk which can be regarded as a stator. The polypeptide called OSCP connects the stator stalk to the assembly of alpha and beta subunits. It is this step that is coupled to proton translocation as energy is required to break the strong bond between ATP and the protein.
R-HSA-164840 (Reactome) The beta subunit has 3 conformations; tight, open and loose. ADP and Pi bind to the subunit in the loose form. On binding, this subunit is converted to the tight configuration.
R-HSA-166214 (Reactome) The FA anion which was facing the matrix side of the inner mitochondrial membrane now flip-flops over to the intermembrane space-side of the membrane.
R-HSA-166215 (Reactome) At the beginning of this reaction, 1 molecule of 'Fatty Acid "head-out"' is present. At the end of this reaction, 1 molecule of 'Fatty Acid "head-in"' is present.

This reaction takes place in the 'mitochondrial inner membrane'.

R-HSA-166219 (Reactome) At the beginning of this reaction, 1 molecule of 'H+', and 1 molecule of 'Fatty Acid anion "head-out"' are present. At the end of this reaction, 1 molecule of 'Fatty Acid "head-out"' is present.

This reaction takes place in the 'mitochondrial inner membrane'.

R-HSA-166220 (Reactome) A FA anion diffuses laterally within the membrane towards UCP. The membrane potential drives the FA anion to an energy well halfway up on UCP. The electric field created by the redox-linked proton ejection drives the head group to the energy well.
R-HSA-166223 (Reactome) At the beginning of this reaction, 1 molecule of 'Fatty Acid "head-in"' is present. At the end of this reaction, 1 molecule of 'H+', and 1 molecule of 'Fatty Acid anion "head-in"' are present.

This reaction takes place in the 'mitochondrial inner membrane'.

R-HSA-166387 (Reactome) At the beginning of this reaction, 1 molecule of 'FA anion:UCP dimer "head-out" complex' is present. At the end of this reaction, 1 molecule of 'UCP dimer', and 1 molecule of 'Fatty Acid anion "head-out"' are present.

This reaction takes place in the 'mitochondrial inner membrane' (Garlid et al. 1996).

R-HSA-169260 (Reactome) Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reducing equivalents from the beta-oxidation of fatty acyl CoAs are transferred to ETF, reducing the ETF-bound FAD to FADH2 (Wood 1999).
R-HSA-169270 (Reactome) ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2) (Estornell et al. 1992, MacLennan et al. 1997).
R-HSA-170026 (Reactome) In this reaction, 1 molecule of 'H+' is translocated from mitochondrial intermembrane space to mitochondrial matrix.

This reaction takes place in the 'mitochondrial inner membrane' and is mediated by the 'hydrogen ion transporter activity' of 'UCP dimer' (Echtay et al. 2002a, Echtay et al. 2002b).
R-HSA-5690023 (Reactome) The iron-sulfur protein NUBPL is thought to bind the cofactor [4Fe-4S] cluster and deliver it to complex I (NADH dehydrogenase) subunits during its biogenesis. The exact mechanism of transfer is unknown but defects in NUBPL are shown to cause mitochondrial complex I deficiency (MT-C1D) with a distinct MRI pattern (Sheftel et al. 2009, Kevelam et al. 2013).
R-HSA-6788523 (Reactome) In total, eight iron-sulfur (4Fe-4S) clusters are incorporated into six subunits (mitochondrial matrix-located NDUFS1, S2, S7, S8 and mitochondrial membrane-located V1 and V2) (Andrews et al. 2013). Incorporation into NDUFV1 and V2 (located on the mitochondrial membrane) is shown in a separate reaction. The mechanism of transfer in all cases is unknown.
R-HSA-6788556 (Reactome) In total, eight iron-sulfur (4Fe-4S) clusters are incorporated into six subunits (mitochondrial matrix-located NDUFS1, S2, S7, S8 and mitochondrial membrane-located V1 and V2) (Andrews et al. 2013). Incorporation into NDUFS1, S2, S7 and S8 is shown in a separate reaction. The mechanism of transfer is unknown. NDUFV1 also binds FMN (Schuelke et al. 1998).
R-HSA-6799178 (Reactome) The hydrophobic protein fraction (HP) is assembled with NDUFA3, 8, 9 and 13 amongst many others and anchored to the inner mitochondrial membrane by Intermediate 1 assembly factors NDUFAF3 (C3orf60), NDUFAF4 (C6orf66) and TIMMDC1 (C3orf1) to form Intermediate 2 (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799179 (Reactome) Subunits NDUFA12, NDUFS1, 4, 6, NDUFV1, 2 and 3 with the assembly factor NDUFAF2 comprises the peripheral arm, called the flavoprotein (FP) subcomplex. In addition, remaining subunits such as NDUFS5 join here (Mimaki et al. 2012).
R-HSA-6799191 (Reactome) A complex I intermediate of 315kDa (reestimated from the original 400kDa) is formed centred around the core subunits NADH dehydrogenase [ubiquinone] iron-sulfur proteins 2 and 3 (NDUFS2 and NDUFS3) with other complex I subunits and assembly factor subunits (forming IP and HP subcomplexes). The IP subcomplex is anchored to the inner mitochondrial membrane by NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) (together with NDUFAF5 and/or 6) (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799196 (Reactome) In the last step, the MCIA complex and it is assumed all of the assembly factors (NDUFAF2-7, TIMMDC1) dissociate from the 980kDa complex to leave mature Complex I (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799197 (Reactome) Distal components of the membrane arm MT-ND4 and 5 associate with the 550kDa complex to form the 815kDa complex (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799199 (Reactome) Membrane arm subunits MT-ND2, 3 and 6 and NDUFB6 associate with the assembly factors TMEM126B, NDUFAF1, ECSIT and ACAD9 (which form the MCIA complex) forming a 370kDa subcomplex (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799202 (Reactome) The 315kDa and 370kDa subcomplexes associate to form a 550kDa complex (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6799203 (Reactome) Complex I assembly begins with the formation of a 315kDa subcomplex, centred around the core subunits NADH dehydrogenase [ubiquinone] iron-sulfur proteins 2 and 3 (NDUFS2 and NDUFS3) (Mckenzie & Ryan 2010, Mimaki et al. 2012, Andrews et al. 2013). NDUFS2 is thought to be bound to NDUFAF7 (Carilla-Latorre et al. 2010). Defects in NDUFS2 can cause mitochondrial complex I deficiency (MT-C1D; OMIM:252010), causing a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders (Loeffen et al. 2001). As an initial part of the 315kDa subcomplex, the subunits NDUFS7, S8 and A9, together with NDUFS2 and S3, form an evolutionarily conserved hydrogenase module as part of the Iron-Sulfur protein fraction (IP) subcomplex (termed Intermediate 1 here) (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6800868 (Reactome) The subunits NDUFS7, S8 and A9, together with NDUFS2 and S3, form an evolutionarily conserved hydrogenase module as part of the Iron-Sulfur protein fraction (IP) subcomplex (Mckenzie & Ryan 2010, Andrews et al. 2013).
R-HSA-6800870 (Reactome) Subunits NDUFA12, NDUFS1, 4, 6, NDUFV1, 2 and 3 with the assembly factor NDUFAF2 comprises the peripheral arm, called the flavoprotein (FP) subcomplex (Mimaki et al. 2012).
R-HSA-9673053 (Reactome) Extracellular PM20D1 (N-fatty-acyl-amino acid synthase/hydrolase PM20D1) catalyzes the reversible condensation of L-phenylalanine (L-phe) and oleate ((9Z)-octadecenoate) to form oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) and water. In addition to the condensation of phe with oleate ((9Z)-octadecenoate) annotated here, purified human PM20D1 protein in vitro can catalyze the condensation of leucine and isoleucine with oleate and other long-chain unsaturated fatty acids including arachidonate, with lower efficiencies. Although the reverse (hydrolysis) direction of this reaction is thermodynamically favored, expression of PM20D1 protein in mice or in cultured cells was associated with elevated levels of oleoyl-phe in serum and culture media, respectively. Treatment of cultured mouse brown adipose tissue adipocytes with oleoyl-phe induced uncoupled respiration independently of UCP1 (uncoupling protein 1) and consistent with this observation, expression of PM20D1 and elevated blood levels of oleoyl-phe in mice were associated with increased energy expenditure and improved glucose homeostasis. These results suggest a physiological role for PM20D1 and its condensation reaction product in thermogenesis and raise the possibility that oleoyl-phe and related molecules might have a clinical role in treatment of obesity (Long et al. 2016).
R-HSA-9673054 (Reactome) Extracellular PM20D1 (N-fatty-acyl-amino acid synthase/hydrolase PM20D1) catalyzes the reversible hydrolysis of oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) to form L-phenylalanine (L-phe) and oleate ((9Z)-octadecenoate). In addition to the hydrolysis of oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) annotated here, purified PM20D1 can hydrolyze a variety of n-acyl amino acids (Long et al. 2016).
SDH complex (ox.)ArrowR-HSA-163213 (Reactome)
Succinate

dehydrogenase

complex (reduced)
R-HSA-163213 (Reactome)
Succinate

dehydrogenase

complex (reduced)
mim-catalysisR-HSA-163213 (Reactome)
TIMMDC1ArrowR-HSA-6799196 (Reactome)
TIMMDC1R-HSA-6799203 (Reactome)
TRAP1TBarR-HSA-163213 (Reactome)
UCP dimerArrowR-HSA-166387 (Reactome)
UCP dimerR-HSA-166220 (Reactome)
UCP dimermim-catalysisR-HSA-170026 (Reactome)
Ubiquinol-cytochrome c reductasemim-catalysisR-HSA-164651 (Reactome)
oleateArrowR-HSA-9673054 (Reactome)
oleateR-HSA-9673053 (Reactome)
oleoyl-PheArrowR-HSA-9673053 (Reactome)
oleoyl-PheR-HSA-9673054 (Reactome)
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