Mitochondrial complex I assembly model OXPHOS system (Homo sapiens)

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MT-ND5NDUFB2NDUFB3NDUFB7NDUFB8NDUFB9NDUFAB1DMAC1NDUFAF21515, 25, 27NDUFS3149, 15229, 15151515, 25, 279159154, 69, 1511, 15579224Complex I assembly:EC 1.6.5.3ND4-module+Timeline of incorporationCOMPLEX 1IMSAdditional subunitsfor final complex formationCHAPERONESND2-moduleQ/ND1-moduleQ-moduleN-moduleFOXRED1MT-ND4NDUFV1COA1TIMMDC1[4Fe-4A]clustersNDUFAF3MT-ND1NDUFA6NDUFS1TMEM126B ?!NDUFA1MT-ND3NDUFAF2Electron Transport Chain PWNDUFA5NDUFA3NDUFB5MT-ND5TMEM186DMAC1NDUFV29CCC9, 17, 204, 13, 18, 2915, 25, 27C153, 26NDUFA2NDUFV1NDUFV2NDUFS1NDUFA2NDUFA7NDUFA12NDUFS4NDUFS6NDUFV3NDUFB10NDUFB11NDUFB6NDUFB5NDUFB10NDUFB11NDUFB6NDUFB1NDUFB4NDUFB5NDUFB10NDUFB11NDUFB6MT-ND4NDUFB1NDUFB4ATP5SLTMEM7015, 269, 12, 13MTND2NDUFC1NDUFC2NDUFAF1ECSIT16, 2319ACAD91, 21MT-ND3MT-ND6MT-ND4LMT-ND6MT-ND4LMTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9MT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9COA19, 17, 20COA1C17, 20CTMEM186C9COA1C17, 20NDUFA10NDUFS5MT-ND6MT-ND4LMT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9NDUFA1NDUFA10NDUFS59, 15TMEM186COA15TMEM126BNDUFAF1ECSIT16, 23ACAD9191, 21NDUFAF6NUBPL8NDUFS2NDUFAF7[4Fe-4A]clustersNUBPL[4Fe-4A]clusters4, 6NDUFS2NDUFS8MM28NDUFAF5NDUFS7NDUFS7COOHNDUFAF4Cnecessary to maintain normal MT-ND1 synthesis10[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS8NDUFS728NDUFAF6NDUFAF38CNDUFAF410C9NDUFA8NDUFA13[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS828NDUFS7NDUFAF68NDUFAF3CNDUFAF410CMT-ND1TIMMDC1C3, 26[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS8NDUFS728NDUFAF6NDUFAF38NDUFAF4C10CMT-ND1TIMMDC13, 26CNDUFA3NDUFA8NDUFA13NDUFB2NDUFB3NDUFB7NDUFB8NDUFB9NDUFAB1ND5-moduleMT-ND5NDUFB2NDUFB3NDUFB7NDUFB8NDUFB9NDUFAB1DMAC115MT-ND6MT-ND4LMT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9NDUFA1NDUFA10NDUFS5COA19, 17, 20COA19, 17, 20TMEM1869COA117, 20TMEM1869COA117, 20FOXRED1ATP5SL4, 13, 18, 29TMEM7015, 26TMEM1869, 12, 13C9COA1C17, 20Mitochondrial Complex I Assembly (MCIA) complex3, 5MT-ND6MT-ND4LMT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9NDUFA1NDUFA10NDUFS5FOXRED14, 13, 18, 29ATP5SLTMEM7015, 269, 12, 13TMEM186C9COA117, 20C[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS8NDUFS728NDUFAF68NDUFAF3CNDUFAF4C10MT-ND1TIMMDC1CNDUFA33, 26NDUFA8NDUFA13MT-ND6MT-ND4LMT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9NDUFA1NDUFA10NDUFS5FOXRED14, 13, 18, 29ATP5SLTMEM7015, 269, 12, 13TMEM1869COA1C17, 20C[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS8NDUFS728NDUFAF6NDUFAF38CNDUFAF410CMT-ND1TIMMDC13, 26NDUFA3CNDUFA8NDUFA13MT-ND5NDUFB2NDUFB3NDUFB7NDUFB8NDUFB9NDUFAB1DMAC115NDUFAF215, 25, 27MT-ND6MT-ND4LMT-ND3MTND2NDUFC1NDUFC2NDUFAF1ECSITACAD9NDUFA1NDUFA10NDUFS5FOXRED14, 13, 18, 29ATP5SL15, 26TMEM70TMEM1869, 12, 13COA1C9C17, 20[4Fe-4A]clustersNDUFS3NDUFA5NDUFS2NDUFS8NDUFS728NDUFAF6NDUFAF38CNDUFAF4C10MT-ND1TIMMDC1C3, 26NDUFA3NDUFA8NDUFA13NDUFA6NDUFA7NDUFA12NDUFS4NDUFS6NDUFV3NDUFV1NDUFV2NDUFS1NDUFA2IMMatrix


Description

This pathway shows how all 45 different subunits are assembled into complex 1 (relevant for the electron transport chain, also known as OXPHOS system), which chaperones(visualised with a small circle and a "C') and which post-translational modifications (a dimethylation on NDUFS2 and hydroxylation on NDUFS7, both in the Q-module) are needed for this assembly.

Most of the steps involved in this intricate process have been described in separate literature references, which have been combined in a review by Alba Signes and Erika Fernandez-Vizarra (DOI: [1]). If possible (based on the size of the protein in KD and available protein structures in Uniprot), the colour of the protein structure drawings have been matched to the annotated protein DataNodes.

Abbreviations: IM, inner membrane; IMS, intermembrane space.

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Bibliography

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  1. Guerrero-Castillo S, Baertling F, Kownatzki D, Wessels HJ, Arnold S, Brandt U, Nijtmans L; ''The Assembly Pathway of Mitochondrial Respiratory Chain Complex I.''; Cell Metab, 2017 PubMed Europe PMC Scholia
  2. Bianciardi L, Imperatore V, Fernandez-Vizarra E, Lopomo A, Falabella M, Furini S, Galluzzi P, Grosso S, Zeviani M, Renieri A, Mari F, Frullanti E; ''Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene.''; Mol Genet Metab, 2016 PubMed Europe PMC Scholia
  3. Vogel RO, van den Brand MA, Rodenburg RJ, van den Heuvel LP, Tsuneoka M, Smeitink JA, Nijtmans LG; ''Investigation of the complex I assembly chaperones B17.2L and NDUFAF1 in a cohort of CI deficient patients.''; Mol Genet Metab, 2007 PubMed Europe PMC Scholia
  4. Nouws J, Nijtmans L, Houten SM, van den Brand M, Huynen M, Venselaar H, Hoefs S, Gloerich J, Kronick J, Hutchin T, Willems P, Rodenburg R, Wanders R, van den Heuvel L, Smeitink J, Vogel RO; ''Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I.''; Cell Metab, 2010 PubMed Europe PMC Scholia
  5. Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT; ''Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease.''; EMBO J, 2007 PubMed Europe PMC Scholia
  6. Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE; ''NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I.''; J Biol Chem, 2016 PubMed Europe PMC Scholia
  7. Hejzlarová K, Mrá�ek T, Vrbacký M, Kaplanová V, Karbanová V, Nůsková H, Pecina P, Houštěk J; ''Nuclear genetic defects of mitochondrial ATP synthase.''; Physiol Res, 2014 PubMed Europe PMC Scholia
  8. Zurita Rendón O, Silva Neiva L, Sasarman F, Shoubridge EA; ''''; , PubMed Europe PMC Scholia
  9. Saada A, Edvardson S, Rapoport M, Shaag A, Amry K, Miller C, Lorberboum-Galski H, Elpeleg O; ''C6ORF66 is an assembly factor of mitochondrial complex I.''; Am J Hum Genet, 2008 PubMed Europe PMC Scholia
  10. Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE; ''NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I.''; J Biol Chem, 2013 PubMed Europe PMC Scholia
  11. Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, Trijbels F, Hamel B, Mullaart R, van den Heuvel L; ''The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.''; Am J Hum Genet, 1998 PubMed Europe PMC Scholia
  12. Stroud DA, Surgenor EE, Formosa LE, Reljic B, Frazier AE, Dibley MG, Osellame LD, Stait T, Beilharz TH, Thorburn DR, Salim A, Ryan MT; ''Accessory subunits are integral for assembly and function of human mitochondrial complex I.''; Nature, 2016 PubMed Europe PMC Scholia
  13. Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, Stroud DA, Ryan MT; ''Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I.''; Hum Mol Genet, 2015 PubMed Europe PMC Scholia
  14. Vogel RO, Janssen RJ, van den Brand MA, Dieteren CE, Verkaart S, Koopman WJ, Willems PH, Pluk W, van den Heuvel LP, Smeitink JA, Nijtmans LG; ''Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly.''; Genes Dev, 2007 PubMed Europe PMC Scholia
  15. Heide H, Bleier L, Steger M, Ackermann J, Dröse S, Schwamb B, Zörnig M, Reichert AS, Koch I, Wittig I, Brandt U; ''Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex.''; Cell Metab, 2012 PubMed Europe PMC Scholia
  16. Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, Gloerich J, Lasonder E, van den Heuvel LP, Nijtmans LG, Huynen MA; ''Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase.''; Genome Biol, 2012 PubMed Europe PMC Scholia
  17. Guarani V, Paulo J, Zhai B, Huttlin EL, Gygi SP, Harper JW; ''TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex.''; Mol Cell Biol, 2014 PubMed Europe PMC Scholia
  18. Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H; ''Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency.''; Nat Genet, 2010 PubMed Europe PMC Scholia
  19. Signes A, Fernandez-Vizarra E; ''Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.''; Essays Biochem, 2018 PubMed Europe PMC Scholia
  20. Zurita Rendón O, Antonicka H, Horvath R, Shoubridge EA; ''A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II.''; Mol Cell Biol, 2016 PubMed Europe PMC Scholia
  21. Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG; ''Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease.''; Am J Hum Genet, 2009 PubMed Europe PMC Scholia
  22. Ogilvie I, Kennaway NG, Shoubridge EA; ''A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy.''; J Clin Invest, 2005 PubMed Europe PMC Scholia
  23. Andrews B, Carroll J, Ding S, Fearnley IM, Walker JE; ''Assembly factors for the membrane arm of human complex I.''; Proc Natl Acad Sci U S A, 2013 PubMed Europe PMC Scholia
  24. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK; ''A mitochondrial protein compendium elucidates complex I disease biology.''; Cell, 2008 PubMed Europe PMC Scholia
  25. Fassone E, Duncan AJ, Taanman JW, Pagnamenta AT, Sadowski MI, Holand T, Qasim W, Rutland P, Calvo SE, Mootha VK, Bitner-Glindzicz M, Rahman S; ''FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy.''; Hum Mol Genet, 2010 PubMed Europe PMC Scholia
  26. Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK; ''High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency.''; Nat Genet, 2010 PubMed Europe PMC Scholia
  27. Sheftel AD, Stehling O, Pierik AJ, Netz DJ, Kerscher S, Elsässer HP, Wittig I, Balk J, Brandt U, Lill R; ''Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I.''; Mol Cell Biol, 2009 PubMed Europe PMC Scholia
  28. Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P; ''MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation.''; Cell, 2012 PubMed Europe PMC Scholia
  29. Vogel RO, Janssen RJ, Ugalde C, Grovenstein M, Huijbens RJ, Visch HJ, van den Heuvel LP, Willems PH, Zeviani M, Smeitink JA, Nijtmans LG; ''Human mitochondrial complex I assembly is mediated by NDUFAF1.''; FEBS J, 2005 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
134817view11:33, 27 July 2024EweitzModified description
134816view11:29, 27 July 2024EweitzImprove margin for big labels, padding for state, standardize case
123506view04:59, 29 July 2022EgonwMade a pathway clickable
98172view13:48, 31 July 2018DeSlChanged location of THMEM126B
98171view11:42, 31 July 2018DeSlModified description
98170view11:42, 31 July 2018DeSlModified description
98169view11:37, 31 July 2018DeSlModified description
98168view11:32, 31 July 2018DeSlAnnotated MT-ND1 (really the last protein without annotation
98167view11:29, 31 July 2018DeSlModified description
98166view11:27, 31 July 2018DeSlAnnotated last protein node, added states to all chaperone nodes.
98165view11:20, 31 July 2018DeSlOntology Term : 'oxidative phosphorylation pathway' added !
98164view11:16, 31 July 2018DeSlAdded linkout to Electron transport chain PW.
98162view11:10, 31 July 2018DeSlModified description
98161view11:06, 31 July 2018DeSlModified description
98160view11:05, 31 July 2018DeSlModified description
98159view11:00, 31 July 2018DeSlOntology Term : 'electron transport chain pathway' added !
98158view10:57, 31 July 2018DeSlNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACAD9ProteinQ9H845 (Uniprot-TrEMBL)
ATP5SLProteinQ9NW81 (Uniprot-TrEMBL)
COA1ProteinQ9GZY4 (Uniprot-TrEMBL) Chaperone
DMAC1ProteinQ96GE9 (Uniprot-TrEMBL)
  • DMAC1/TMEM261 is implicated in the stabilization and/or assembly of the ND5-module
  • 11,8 KD
ECSITProteinQ9BQ95 (Uniprot-TrEMBL)
Electron Transport Chain PWPathwayWP111 (WikiPathways)
FOXRED1ProteinQ96CU9 (Uniprot-TrEMBL)
MT-ND1ProteinP03886 (Uniprot-TrEMBL)
MT-ND3ProteinQ9GZY4 (Uniprot-TrEMBL)
MT-ND4LProteinP03901 (Uniprot-TrEMBL) 11 KD
MT-ND4ProteinP03905 (Uniprot-TrEMBL) 52 Kda
MT-ND5ProteinP03915 (Uniprot-TrEMBL) 67 KD
MT-ND6ProteinP03923 (Uniprot-TrEMBL) 18 KD
MTND2ProteinP03891 (Uniprot-TrEMBL)
NDUFA10ProteinO95299 (Uniprot-TrEMBL) 41KD
NDUFA12ProteinQ9UI09 (Uniprot-TrEMBL)
NDUFA13ProteinQ9P0J0 (Uniprot-TrEMBL) 17 kD
NDUFA1ProteinO15239 (Uniprot-TrEMBL) 8.1 KD
NDUFA2ProteinO43678 (Uniprot-TrEMBL)
NDUFA3ProteinO95167 (Uniprot-TrEMBL) 9.3 KD
NDUFA5ProteinQ16718 (Uniprot-TrEMBL) 13.5 KD
NDUFA6ProteinP56556 (Uniprot-TrEMBL)
NDUFA7ProteinO95182 (Uniprot-TrEMBL)
NDUFA8ProteinP51970 (Uniprot-TrEMBL) 20 kD
NDUFAB1ProteinO14561 (Uniprot-TrEMBL) ~16 KD
NDUFAF1ProteinQ9Y375 (Uniprot-TrEMBL)
NDUFAF2ProteinQ8N183 (Uniprot-TrEMBL) Stabilising intermediated only lacking the N-module
NDUFAF3ProteinQ9BU61 (Uniprot-TrEMBL)
  • Chaperone
  • Remain bound to this module until the final assembly steps
NDUFAF4ProteinQ9P032 (Uniprot-TrEMBL)
  • Chaperone
  • Remain bound to this module until the final assembly steps
NDUFAF5ProteinQ (Uniprot-TrEMBL)
NDUFAF6ProteinQ330K2 (Uniprot-TrEMBL)
  • 38.2 kDa
  • seems to participate in the assembly of the Q-module
  • necessary to maintain normal MT-ND1 synthesis
NDUFAF7ProteinQ7L592 (Uniprot-TrEMBL) 49.2 kD (proteinatlas)
NDUFB10ProteinO96000 (Uniprot-TrEMBL)
NDUFB11ProteinQ9NX14 (Uniprot-TrEMBL)
NDUFB1ProteinO75438 (Uniprot-TrEMBL) 7 KD
NDUFB2ProteinO95178 (Uniprot-TrEMBL) 12 KD
NDUFB3ProteinO43676 (Uniprot-TrEMBL) ~12 KD
NDUFB4ProteinO95168 (Uniprot-TrEMBL)
  • 15 Kd
  • Not believed to be involved in catalysis
NDUFB5ProteinO43674 (Uniprot-TrEMBL)
NDUFB6ProteinO95139 (Uniprot-TrEMBL)
NDUFB7ProteinP17568 (Uniprot-TrEMBL) 16.4 KD
NDUFB8ProteinO95169 (Uniprot-TrEMBL) 22 KD
NDUFB9ProteinQ9Y6M9 (Uniprot-TrEMBL) 22 KD
NDUFC1ProteinO43677 (Uniprot-TrEMBL)
NDUFC2ProteinO95298 (Uniprot-TrEMBL)
NDUFS1ProteinP28331 (Uniprot-TrEMBL)
NDUFS2ProteinO75306 (Uniprot-TrEMBL) 49 KD
NDUFS3ProteinO75489 (Uniprot-TrEMBL) 30.2 KDa (protein atlas)
NDUFS4ProteinO43181 (Uniprot-TrEMBL)
NDUFS5ProteinO43920 (Uniprot-TrEMBL) 15KD
NDUFS6ProteinO75380 (Uniprot-TrEMBL)
NDUFS7ProteinO (Uniprot-TrEMBL) 20 kD
NDUFS8ProteinO (Uniprot-TrEMBL)
  • 23,7 KD
  • The encoded protein(TYKY) contains two [4Fe-4S] ferredoxin consensus patterns [PMID: 9837812]
NDUFV1ProteinP49821 (Uniprot-TrEMBL)
NDUFV2ProteinP19404 (Uniprot-TrEMBL)
NDUFV3ProteinP56181 (Uniprot-TrEMBL)
NUBPLProteinQ8TB37 (Uniprot-TrEMBL)
TIMMDC1ProteinQ9NPL8 (Uniprot-TrEMBL)
  • aka C3ORF1
  • Chaperone
  • remains bound to the Q/ND1 subassembly until the last maturation steps.
TMEM126B ?!ProteinQ8IUX1 (Uniprot-TrEMBL) Not in Figure at first step, but written down in text!
TMEM126BProteinQ8IUX1 (Uniprot-TrEMBL) Not in Figure at first step, but written down in text!
TMEM186ProteinQ96B77 (Uniprot-TrEMBL) Chaperone
TMEM70ProteinQ9BUB7 (Uniprot-TrEMBL) aka cV assembly factor
[4Fe-4A] clustersMetaboliteCHEBI:64607 (ChEBI)

Annotated Interactions

No annotated interactions

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