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

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16, 291, 445, 87, 45142, 1516, 297, 457, 45207, 4516, 29291416, 2924, 25, 349, 16, 18, 29, 3616, 2916, 2916, 2926, 304, 6, 12, 17, 21...3, 45367, 451423, 28, 32, 33, 35...11, 2936mitochondrial intermembrane spacemitochondrial matrixH+UCP1 NDUFS2 NDUFAF24Fe-4S ATP5C1 4Fe-4S NDUFB2 ATP NDUFA11 TIMMDC1 NDUFS7 NDUFAB1 NAD+NDUFAF5 NDUFAF3 NDUFAF5ATP5F1 ATP5G2 ATP5E 315kDa subcomplexNDUFB9 NDUFA10 NDUFA13 COX7A2L NDUFA3 ATP5I Fatty Acid anion "head-out" NDUFB3 CuA COX6A1 ATP5J COX ancilliaryproteinsATPase:ADP:PiCYC1 FAD NDUFB7 ACAD9 COX16 SLC25A27 NDUFV2 NDUFA11 SDHC ATP5B SURF1 NDUFS6FAD MT-ND5 NDUFS8 NDUFA13 NDUFA9 NDUFB4 NDUFS2 NDUFB10 NDUFAF7 NDUFAF7 HP subcomplexCOX5A COQ10A,BNDUFA7 NDUFS3 NDUFAF4 MT-ND1 NDUFS7 MT-ND6GTP FMN TACO1 ATP5L NDUFV1 NDUFAF3 NDUFB5 NDUFC1 Fatty Acid"head-out"NDUFA12 4Fe-4S ATP5J2 Iron Sulphur Cluster NDUFAF5 NDUFA8 NDUFA6 NDUFB8 FAD NDUFAF7 Heme 1 cytochrome c1 cofactor CYCS 4Fe-4S NDUFB10 NDUFB8 TIMMDC1NDUFA10 NDUFAF5 NDUFA2 NDUFA11 NDUFB10 FAD Pi MT-ND5 NDUFA1 NDUFA6 NDUFC1 Cytochrome c oxidaseNDUFA1 ATP5D NDUFS5 NDUFB1 FADNDUFB11 SCO2 NDUFV1 NDUFS8:2x4Fe-4SNDUFS5 NDUFB9 NDUFS1 MT-ND6 NDUFS7 NDUFV1 QH2NDUFB11 MT-ND4 NDUFB3 NDUFS2 MCIA complex4Fe-4S H+NDUFA11 NDUFA9 NDUFB2 NDUFC2 ADP NDUFB5 NDUFA10 CoQNDUFA3 NDUFAF6 MT-ND1 NDUFB4 NDUFAF4 NDUFS8 NDUFA1 FAD NDUFAF7NDUFAF5 ATP5G1 SLC25A14 ATP5G1 CYCS NDUFAF3 Fatty Acid "head-in"NDUFA7 Heme 2 cytochrome c1 cofactor NDUFA12NDUFS8 NDUFS7 COX6C(3-75) NDUFAF4 4Fe-4S ATP5O ACAD9 UQCRQ 4Fe-4S 4Fe-4S NDUFC1 NDUFS7 NDUFS2 FADH2 ETFDHNDUFA13 MT-ND2 SDHB 980kDa complexTMEM126B NDUFA8 MT-ND3 UCP1 NDUFS3 NDUFB3 MT-ND6 NDUFAF1 NDUFA5 NDUFC2 NDUFAF7:NDUFS2:2x4Fe-4SNDUFC2 NDUFS7 NDUFB2 NDUFA2 NDUFA5 4Fe-4S NDUFS2 ATP5C1 NDUFS1 NDUFC1 NDUFC2 ATP5D NDUFA5 ATP5J2 NUBPLH+ADPNDUFB9 MT-ATP8 COX14 COX18 NDUFAF6 NDUFAF3 NDUFA3 NDUFS8 NDUFAF6 NDUFA9 NDUFA5 TMEM126B TMEM126B NDUFB8 NDUFA2 MT-ND3 QH2NDUFC1 NDUFS3ATP5J2 NDUFS8 NDUFB11 Complex IFAD NDUFB7 NDUFB6 COQ10B NDUFS7 NDUFA2 ATP5L NDUFB4 NDUFB7 NDUFB6 NDUFB8 NDUFAB1 NDUFS2 NDUFS8 4Fe-4S NDUFV3NDUFAB1 NDUFA9 ATP5E COX11 ferroheme Purine nucleotideCoQNDUFS4 UQCRFS1(79-274) NDUFV2 ECSIT H2OMT-ND2 NUBPL:4Fe-4SNDUFAF1 NDUFS3 NDUFA2 NDUFS2 IP subcomplexATP5G3 ATP5E NDUFA6 NDUFAF7 NDUFB5 MT-ND3NDUFS4 NDUFA10 ETF:FADH2NDUFB1 NDUFS7:4Fe-4SMT-ATP6 MT-ND1 MT-ATP6 ATP5D MT-CO2 NDUFAF7 TRAP1NDUFAF7 ATP5O NDUFA3 TMEM126B NDUFB8 NDUFA13 NDUFS54Fe-4S COX5B H+NDUFB2 SCO1 H+NDUFA10 MT-ND2 MT-CO1 NDUFAF4NDUFB5 NDUFAB1 Intermediate 2NDUFS8 NDUFB8 FADH2ATP5H NDUFA7 MT-ND6 NDUFS6 4Fe-4S TIMMDC1 NDUFA13 NDUFS7 ATP5A1 NDUFS7 SLC25A27 MT-ND1 CYCS ADP NDUFB11 NDUFAB1 NDUFB1 MT-CYB SDHB NDUFB5 FAD ATP5A1 Fatty Acid anion"head-out"MT-ND3 370 kDa subcomplex4Fe-4S NDUFA12 Fatty Acid anion "head-in" NDUFC2 NDUFV3 NDUFA2 NDUFB9 ATP5L UQCRC2 NDUFA8 SDHC ATP5S NDUFAF6 MT-ND1 NDUFS8 TIMMDC1 NDUFS3 NDUFAF3 UCP1 NDUFA8 Ubiquinol-cytochromec reductaseUCP3 ECSIT COX4I1 ATP5B UCP1 SLC25A14 Cytochrome c(oxidised)NDUFB9 UCP2 Heme bL ETFA(1-?) FAD NDUFA7 NDUFAF1 NDUFV1MT-ATP6 TIMMDC1 NDUFAF7 NDUFB2 NDUFAF3 Ketone bodymetabolismCytochrome c(reduced)NDUFAF4 NDUFA2 NDUFB1 MT-ND5ATP5G2 NDUFA9 NDUFA5 NDUFAF4 NDUFB1 FAD FAD FAD NDUFB2 QH2TIMMDC1 ATP5G3 NDUFB5 ATP5F1 NDUFS8 ATP5S NDUFB6 FMN NDUFAF2 NDUFV2 NDUFB4 NDUF:4Fe-4S subunits4Fe-4SNDUFB8 UCP3 H2ONDUFB10 NDUFAF1 COX8A ETFB NDUFS2 COX6B1 NDUFA3 SLC25A27 Succinatedehydrogenasecomplex (reduced)NDUFB7 NDUFV2:4Fe-4SUQCRH NDUFC2 NDUFC1 NDUFA11 NDUFB11 UCP2 GDP adenosine 5'-monophosphate NDUFB6 SDHA 815kDa complexATP5A1 NDUFA4 F1Fo ATP synthaseMT-ND2ACAD9 NDUFA1 NDUFS7 UCP2 NDUFA6 NDUFS3 NDUFB3 COX7C NDUFB3 Cytochrome c(oxidised)NDUFB3 COX20 CoQATP5H MT-ND6 FMNATP5B ATP5C1 ACAD9 FMN ACAD9 MT-ND5 ATP5I NDUFA7 NDUFB11 SLC25A14 NDUFV2 NDUFAF7 NDUFA8 ATP5I NDUFV3 ECSIT UQCR11 NDUFB1 SLC25A14 TMEM126B Intermediate 1NDUFB4 ETFB NDUFB10 UCP3 NDUFS2 ATP5G2 UCP3 NDUFA8 NDUFA9 COX19ATP FA anion:UCP dimer"head-in" complexETFA(1-?) NDUFB2 NDUFA9 NDUFS1 NDUFAF6MT-ND3 UQCRB NDUFC1 NADHNDUFB6LRPPRC NDUFB10 NDUF subunitsNDUFB7 NDUFS2 NDUFA9 NDUFAF4 ATP5F1 SDHA 550kDa complexNDUFA7 MT-ND6 NDUFS1 4Fe-4S NDUFA3 NDUFB5 H+NDUFS3 O24Fe-4S UQCR10 ATP5O NDUFB7 FA anion:UCP dimer "head-out" complexNDUFAF1 NDUFA12 CoQUCP2 NDUFB9 ATP5G3 NUBPL NDUFB4 COX7B NDUFA11 NDUFA9:FADFatty Acid anion"head-in"ATP5S NDUFA5 MT-ATP8 NDUFAF3NDUFS3 NDUFAF2 UCP dimerNDUFA6 H+COX11,14,16,18,20NDUFB10 4Fe-4S SDH complex (ox.)NDUFS1:2x4Fe-4S4Fe-4S SDHD FAD NDUFS7 NDUFV1:4Fe-4S:FMNNDUFAB1 SDHD MT-ND4NDUFA1 NDUFS8 NDUFS2 FAD ferriheme NDUFA9 NDUFS3 NDUFA8 4Fe-4S PiNDUFV2ATP5J FP subcomplexNDUFS1 ATP5G1 NDUFC2 ETF:FADadenosine 5'-monophosphate MT-CO3 LCFAMT-ND2 H+FAD NDUFB4 NDUFA5 NDUFA13 NDUFB1 ferriheme TIMMDC1 SLC25A27 NDUFA1 MT-ND3 NDUFS8 ATPFAD NDUFS6 MT-ND2 Iron Sulphur Cluster Mitochondrial FattyAcid Beta-OxidationNDUFA7 NDUFAB1 FAD H+ATPase:ATPNDUFA1 NDUFA6 NDUFA10 UCP dimerNDUFA3 2Fe-2S NDUFA11 NDUFB6 ATP5H NDUFB9 NDUFA6 NDUFA13 NDUFB11 MT-ND4 ECSIT NDUFS4 FAD NDUFS1 NDUFB3 ECSIT FAD MT-ND4 MT-ND1NDUFS6 UQCRC1 4Fe-4S FADH2 NDUFV3 NDUFA10 NDUFS4NDUFB7 COQ10A FMN MT-ATP8 ATP5J NDUFV1 4Fe-4S 10, 19, 27, 421322, 41


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: 65
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:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP MetaboliteCHEBI:15422 (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:15422 (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).

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:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (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)
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)

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)
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)
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)
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).
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)
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