Mitochondrial complex I assembly model OXPHOS system (WP4324)

Homo sapiens

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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 (visualized 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[https://doi.org/10.1042/EBC20170098]. If possible (based on the size of the protein in KD and available protein structures in Uniprot), the color of the protein structure drawings have been matched to the annotated protein DataNodes. Abbreviations: IM, inner membrane; IMS, intermembrane space.

Authors

Denise Slenter , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Serious Request 2024 - MetaKids

Annotations

Pathway Ontology

oxidative phosphorylation pathway electron transport chain pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
[4Fe-4A]clusters Metabolite chebi:64607
MT-ND5 Protein uniprot:P03915 67 KD
NDUFB2 Protein uniprot:O95178 12 KD
NDUFB3 Protein uniprot:O43676 ~12 KD
NDUFB7 Protein uniprot:P17568 16.4 KD
NDUFB8 Protein uniprot:O95169 22 KD
NDUFB9 Protein uniprot:Q9Y6M9 22 KD
NDUFAB1 Protein uniprot:O14561 ~16 KD
DMAC1 Protein uniprot:Q96GE9 DMAC1/TMEM261 is implicated in the stabilization and/or assembly of the ND5-module
11,8 KD
NDUFAF2 Protein uniprot:Q8N183 Stabilising intermediated only lacking the N-module
NDUFS3 Protein uniprot:O75489 30.2 KDa (protein atlas)
NDUFB5 Protein uniprot:O43674
TIMMDC1 Protein uniprot:Q9NPL8 aka C3ORF1
Chaperone
remains bound to the Q/ND1 subassembly until the last maturation steps.
MT-ND4 Protein uniprot:P03905 52 Kda
NDUFAF3 Protein uniprot:Q9BU61 Chaperone
FOXRED1 Protein uniprot:Q96CU9
NDUFV1 Protein uniprot:P49821
NDUFA5 Protein uniprot:Q16718 13.5 KD
MT-ND1 Protein uniprot:P03886
NDUFA1 Protein uniprot:O15239 8.1 KD
COA1 Protein uniprot:Q9GZY4 Chaperone
MT-ND3 Protein uniprot:Q9GZY4
TMEM126B Protein uniprot:Q8IUX1 Not in Figure at first step, but written down in text!
NDUFS1 Protein uniprot:P28331
TMEM186 Protein uniprot:Q96B77 Chaperone
NDUFA6 Protein uniprot:P56556
NDUFA3 Protein uniprot:O95167 9.3 KD
NDUFV2 Protein uniprot:P19404
NDUFA2 Protein uniprot:O43678
NDUFA7 Protein uniprot:O95182
NDUFA12 Protein uniprot:Q9UI09
NDUFS4 Protein uniprot:O43181
NDUFS6 Protein uniprot:O75380
NDUFV3 Protein uniprot:P56181
NDUFB10 Protein uniprot:O96000
NDUFB11 Protein uniprot:Q9NX14
NDUFB6 Protein uniprot:O95139
NDUFB1 Protein uniprot:O75438 7 KD
NDUFB4 Protein uniprot:O95168 15 Kd
Not believed to be involved in catalysis
ATP5SL Protein uniprot:Q9NW81
TMEM70 Protein uniprot:Q9BUB7 aka cV assembly factor
MTND2 Protein uniprot:P03891
NDUFC1 Protein uniprot:O43677
NDUFC2 Protein uniprot:O95298
NDUFAF1 Protein uniprot:Q9Y375 aka CIA30
ECSIT Protein uniprot:Q9BQ95
ACAD9 Protein uniprot:Q9H845
MT-ND6 Protein uniprot:P03923 18 KD
MT-ND4L Protein uniprot:P03901 11 KD
NDUFAF1 Protein uniprot:Q9Y375
NDUFA10 Protein uniprot:O95299 41KD
NDUFS5 Protein uniprot:O43920 15KD
TMEM186 Protein uniprot:Q96B77
COA1 Protein uniprot:Q9GZY4
NDUFAF6 Protein uniprot:Q330K2 38.2 kDa
seems to participate in the assembly of the Q-module
necessary to maintain normal MT-ND1 synthesis
NUBPL Protein uniprot:Q8TB37
NDUFS2 Protein uniprot:O75306 49 KD
NDUFAF7 Protein uniprot:Q7L592 49.2 kD (proteinatlas)
NDUFS8 Protein uniprot:O 23,7 KD
The encoded protein(TYKY) contains two [4Fe-4S] ferredoxin consensus patterns [PMID: 9837812]
NDUFAF5 Protein uniprot:Q
NDUFS7 Protein uniprot:O 20 kD
NDUFS7 Protein uniprot:O
NDUFAF4 Protein uniprot:Q9P032 Chaperone
NDUFAF3 Protein uniprot:Q9BU61 Chaperone
Remain bound to this module until the final assembly steps
NDUFAF4 Protein uniprot:Q9P032 Chaperone
Remain bound to this module until the final assembly steps
NDUFA8 Protein uniprot:P51970 20 kD
NDUFA13 Protein uniprot:Q9P0J0 17 kD

References

  1. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, et al. Am J Hum Genet. 1998 Dec;63(6):1598–608. PubMed Europe PMC Scholia
  2. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. Ogilvie I, Kennaway NG, Shoubridge EA. J Clin Invest. 2005 Oct;115(10):2784–92. PubMed Europe PMC Scholia
  3. Human mitochondrial complex I assembly is mediated by NDUFAF1. Vogel RO, Janssen RJRJ, Ugalde C, Grovenstein M, Huijbens RJ, Visch HJ, et al. FEBS J. 2005 Oct;272(20):5317–26. PubMed Europe PMC Scholia
  4. Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly. Vogel RO, Janssen RJRJ, van den Brand MAM, Dieteren CEJ, Verkaart S, Koopman WJH, et al. Genes Dev. 2007 Mar 1;21(5):615–24. PubMed Europe PMC Scholia
  5. Investigation of the complex I assembly chaperones B17.2L and NDUFAF1 in a cohort of CI deficient patients. Vogel RO, van den Brand MAM, Rodenburg RJ, van den Heuvel LPWJ, Tsuneoka M, Smeitink JAM, et al. Mol Genet Metab. 2007 Jun;91(2):176–82. PubMed Europe PMC Scholia
  6. Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. Dunning CJR, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, et al. EMBO J. 2007 Jul 11;26(13):3227–37. PubMed Europe PMC Scholia
  7. C6ORF66 is an assembly factor of mitochondrial complex I. Saada A, Edvardson S, Rapoport M, Shaag A, Amry K, Miller C, et al. Am J Hum Genet. 2008 Jan;82(1):32–8. PubMed Europe PMC Scholia
  8. A mitochondrial protein compendium elucidates complex I disease biology. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, et al. Cell. 2008 Jul 11;134(1):112–23. PubMed Europe PMC Scholia
  9. Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, et al. Am J Hum Genet. 2009 Jun;84(6):718–27. PubMed Europe PMC Scholia
  10. Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I. Sheftel AD, Stehling O, Pierik AJ, Netz DJA, Kerscher S, Elsässer HP, et al. Mol Cell Biol. 2009 Nov;29(22):6059–73. PubMed Europe PMC Scholia
  11. Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Nouws J, Nijtmans L, Houten SM, van den Brand M, Huynen M, Venselaar H, et al. Cell Metab. 2010 Sep 8;12(3):283–94. PubMed Europe PMC Scholia
  12. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, et al. Nat Genet. 2010 Oct;42(10):851–8. PubMed Europe PMC Scholia
  13. FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. Fassone E, Duncan AJ, Taanman JW, Pagnamenta AT, Sadowski MI, Holand T, et al. Hum Mol Genet. 2010 Dec 15;19(24):4837–47. PubMed Europe PMC Scholia
  14. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, et al. Nat Genet. 2010 Dec;42(12):1131–4. PubMed Europe PMC Scholia
  15. 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. Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, et al. Genome Biol. 2012 Feb 22;13(2):R12. PubMed Europe PMC Scholia
  16. Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex. Heide H, Bleier L, Steger M, Ackermann J, Dröse S, Schwamb B, et al. Cell Metab. 2012 Oct 3;16(4):538–49. PubMed Europe PMC Scholia
  17. MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, et al. Cell. 2012 Dec 21;151(7):1528–41. PubMed Europe PMC Scholia
  18. NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I. Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE. J Biol Chem. 2013 Nov 15;288(46):33016–26. PubMed Europe PMC Scholia
  19. Assembly factors for the membrane arm of human complex I. Andrews B, Carroll J, Ding S, Fearnley IM, Walker JE. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18934–9. PubMed Europe PMC Scholia
  20. TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex. Guarani V, Paulo J, Zhai B, Huttlin EL, Gygi SP, Harper JW. Mol Cell Biol. 2014 Mar;34(5):847–61. PubMed Europe PMC Scholia
  21. Nuclear genetic defects of mitochondrial ATP synthase. Hejzlarová K, Mráček T, Vrbacký M, Kaplanová V, Karbanová V, Nůsková H, et al. Physiol Res. 2014;63(Suppl 1):S57-71. PubMed Europe PMC Scholia
  22. The arginine methyltransferase NDUFAF7 is essential for complex I assembly and early vertebrate embryogenesis. Zurita Rendón O, Silva Neiva L, Sasarman F, Shoubridge EA. Hum Mol Genet. 2014 Oct 1;23(19):5159–70. PubMed Europe PMC Scholia
  23. Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I. Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, et al. Hum Mol Genet. 2015 May 15;24(10):2952–65. PubMed Europe PMC Scholia
  24. A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II. Zurita Rendón O, Antonicka H, Horvath R, Shoubridge EA. Mol Cell Biol. 2016 Jul 29;36(16):2132–40. PubMed Europe PMC Scholia
  25. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I. Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE. J Biol Chem. 2016 Jul 8;291(28):14851–60. PubMed Europe PMC Scholia
  26. Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene. Bianciardi L, Imperatore V, Fernandez-Vizarra E, Lopomo A, Falabella M, Furini S, et al. Mol Genet Metab. 2016 Nov;119(3):214–22. PubMed Europe PMC Scholia
  27. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Stroud DA, Surgenor EE, Formosa LE, Reljic B, Frazier AE, Dibley MG, et al. Nature. 2016 Oct 6;538(7623):123–6. PubMed Europe PMC Scholia
  28. The Assembly Pathway of Mitochondrial Respiratory Chain Complex I. Guerrero-Castillo S, Baertling F, Kownatzki D, Wessels HJ, Arnold S, Brandt U, et al. Cell Metab. 2017 Jan 10;25(1):128–39. PubMed Europe PMC Scholia
  29. Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes. Signes A, Fernandez-Vizarra E. Essays Biochem. 2018 Jul 20;62(3):255–70. PubMed Europe PMC Scholia