Mitochondrial protein import (Homo sapiens)

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1. van der Laan M, Hutu DP, Rehling P.; ''On the mechanism of preprotein import by the mitochondrial presequence translocase.''; PubMed Europe PMC Scholia
2. Roesch K, Hynds PJ, Varga R, Tranebjaerg L, Koehler CM.; ''The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex.''; PubMed Europe PMC Scholia
3. Sakowska P, Jans DC, Mohanraj K, Riedel D, Jakobs S, Chacinska A.; ''The Oxidation Status of Mic19 Regulates MICOS Assembly.''; PubMed Europe PMC Scholia
4. Banci L, Bertini I, Ciofi-Baffoni S, Janicka A, Martinelli M, Kozlowski H, Palumaa P.; ''A structural-dynamical characterization of human Cox17.''; PubMed Europe PMC Scholia
5. Endo T, Yamano K.; ''Multiple pathways for mitochondrial protein traffic.''; PubMed Europe PMC Scholia
6. Teixeira PF, Pinho CM, Branca RM, Lehtiö J, Levine RL, Glaser E.; ''In vitro oxidative inactivation of human presequence protease (hPreP).''; PubMed Europe PMC Scholia
7. De Marcos Lousa C, Trézéguet V, Dianoux AC, Brandolin G, Lauquin GJ.; ''The human mitochondrial ADP/ATP carriers: kinetic properties and biogenesis of wild-type and mutant proteins in the yeast S. cerevisiae.''; PubMed Europe PMC Scholia
8. Deponte M, Hell K.; ''Disulphide bond formation in the intermembrane space of mitochondria.''; PubMed Europe PMC Scholia
9. Milenkovic D, Müller J, Stojanovski D, Pfanner N, Chacinska A.; ''Diverse mechanisms and machineries for import of mitochondrial proteins.''; PubMed Europe PMC Scholia
10. Sideris DP, Tokatlidis K.; ''Oxidative protein folding in the mitochondrial intermembrane space.''; PubMed Europe PMC Scholia
11. Flick MJ, Konieczny SF.; ''Identification of putative mammalian D-lactate dehydrogenase enzymes.''; PubMed Europe PMC Scholia
12. Humphries AD, Streimann IC, Stojanovski D, Johnston AJ, Yano M, Hoogenraad NJ, Ryan MT.; ''Dissection of the mitochondrial import and assembly pathway for human Tom40.''; PubMed Europe PMC Scholia
13. Di Fonzo A, Ronchi D, Lodi T, Fassone E, Tigano M, Lamperti C, Corti S, Bordoni A, Fortunato F, Nizzardo M, Napoli L, Donadoni C, Salani S, Saladino F, Moggio M, Bresolin N, Ferrero I, Comi GP.; ''The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency.''; PubMed Europe PMC Scholia
14. Baertling F, A M van den Brand M, Hertecant JL, Al-Shamsi A, P van den Heuvel L, Distelmaier F, Mayatepek E, Smeitink JA, Nijtmans LG, Rodenburg RJ.; ''Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.''; PubMed Europe PMC Scholia
15. Zhang Y, Deng H, Zhao Q, Li SJ.; ''Interaction of presequence peptides with human translocase of inner membrane of mitochondria Tim23.''; PubMed Europe PMC Scholia
16. Fischer M, Horn S, Belkacemi A, Kojer K, Petrungaro C, Habich M, Ali M, Küttner V, Bien M, Kauff F, Dengjel J, Herrmann JM, Riemer J.; ''Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells.''; PubMed Europe PMC Scholia
17. Xie J, Marusich MF, Souda P, Whitelegge J, Capaldi RA.; ''The mitochondrial inner membrane protein mitofilin exists as a complex with SAM50, metaxins 1 and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and DnaJC11.''; PubMed Europe PMC Scholia
18. Bauer MF, Gempel K, Reichert AS, Rappold GA, Lichtner P, Gerbitz KD, Neupert W, Brunner M, Hofmann S.; ''Genetic and structural characterization of the human mitochondrial inner membrane translocase.''; PubMed Europe PMC Scholia
19. Yamano K, Kuroyanagi-Hasegawa M, Esaki M, Yokota M, Endo T.; ''Step-size analyses of the mitochondrial Hsp70 import motor reveal the Brownian ratchet in operation.''; PubMed Europe PMC Scholia
20. Yamamoto H, Fukui K, Takahashi H, Kitamura S, Shiota T, Terao K, Uchida M, Esaki M, Nishikawa S, Yoshihisa T, Yamano K, Endo T.; ''Roles of Tom70 in import of presequence-containing mitochondrial proteins.''; PubMed Europe PMC Scholia
21. Brunetti D, Torsvik J, Dallabona C, Teixeira P, Sztromwasser P, Fernandez-Vizarra E, Cerutti R, Reyes A, Preziuso C, D'Amati G, Baruffini E, Goffrini P, Viscomi C, Ferrero I, Boman H, Telstad W, Johansson S, Glaser E, Knappskog PM, Zeviani M, Bindoff LA.; ''Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.''; PubMed Europe PMC Scholia
22. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore DG, Verschueren A, Rouzier C, Le Ber I, Augé G, Cochaud C, Lespinasse F, N'Guyen K, de Septenville A, Brice A, Yu-Wai-Man P, Sesaki H, Pouget J, Paquis-Flucklinger V.; ''A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.''; PubMed Europe PMC Scholia
23. Farrell SR, Thorpe C.; ''Augmenter of liver regeneration: a flavin-dependent sulfhydryl oxidase with cytochrome c reductase activity.''; PubMed Europe PMC Scholia
24. Dabir DV, Hasson SA, Setoguchi K, Johnson ME, Wongkongkathep P, Douglas CJ, Zimmerman J, Damoiseaux R, Teitell MA, Koehler CM.; ''A small molecule inhibitor of redox-regulated protein translocation into mitochondria.''; PubMed Europe PMC Scholia
25. Kang Y, Fielden LF, Stojanovski D.; ''Mitochondrial protein transport in health and disease.''; PubMed Europe PMC Scholia
26. Webb CT, Gorman MA, Lazarou M, Ryan MT, Gulbis JM.; ''Crystal structure of the mitochondrial chaperone TIM9.10 reveals a six-bladed alpha-propeller.''; PubMed Europe PMC Scholia
27. Kutik S, Guiard B, Meyer HE, Wiedemann N, Pfanner N.; ''Cooperation of translocase complexes in mitochondrial protein import.''; PubMed Europe PMC Scholia
28. Banci L, Bertini I, Ciofi-Baffoni S, Jaiswal D, Neri S, Peruzzini R, Winkelmann J.; ''Structural characterization of CHCHD5 and CHCHD7: two atypical human twin CX9C proteins.''; PubMed Europe PMC Scholia
29. Kozjak-Pavlovic V, Ross K, Benlasfer N, Kimmig S, Karlas A, Rudel T.; ''Conserved roles of Sam50 and metaxins in VDAC biogenesis.''; PubMed Europe PMC Scholia
30. Li K, Warner CK, Hodge JA, Minoshima S, Kudoh J, Fukuyama R, Maekawa M, Shimizu Y, Shimizu N, Wallace DC.; ''A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed.''; PubMed Europe PMC Scholia
31. Mühlenbein N, Hofmann S, Rothbauer U, Bauer MF.; ''Organization and function of the small Tim complexes acting along the import pathway of metabolite carriers into mammalian mitochondria.''; PubMed Europe PMC Scholia
32. Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS.; ''Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria.''; PubMed Europe PMC Scholia
33. Wiedemann N, Pfanner N.; ''Mitochondrial Machineries for Protein Import and Assembly.''; PubMed Europe PMC Scholia
34. Liu Y, Clegg HV, Leslie PL, Di J, Tollini LA, He Y, Kim TH, Jin A, Graves LM, Zheng J, Zhang Y.; ''CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation.''; PubMed Europe PMC Scholia
35. Pacheu-Grau D, Bareth B, Dudek J, Juris L, Vögtle FN, Wissel M, Leary SC, Dennerlein S, Rehling P, Deckers M.; ''Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.''; PubMed Europe PMC Scholia
36. 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.''; PubMed Europe PMC Scholia
37. Hofmann S, Rothbauer U, Mühlenbein N, Baiker K, Hell K, Bauer MF.; ''Functional and mutational characterization of human MIA40 acting during import into the mitochondrial intermembrane space.''; PubMed Europe PMC Scholia
38. Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E.; ''Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP.''; PubMed Europe PMC Scholia
39. Stojanovski D, Müller JM, Milenkovic D, Guiard B, Pfanner N, Chacinska A.; ''The MIA system for protein import into the mitochondrial intermembrane space.''; PubMed Europe PMC Scholia
40. Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C.; ''Genetic and biochemical studies of SNPs of the mitochondrial A beta-degrading protease, hPreP.''; PubMed Europe PMC Scholia
41. Aras S, Bai M, Lee I, Springett R, Hüttemann M, Grossman LI.; ''MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism.''; PubMed Europe PMC Scholia
42. Sinha D, Srivastava S, Krishna L, D'Silva P.; ''Unraveling the intricate organization of mammalian mitochondrial presequence translocases: existence of multiple translocases for maintenance of mitochondrial function.''; PubMed Europe PMC Scholia
43. Sinha D, Joshi N, Chittoor B, Samji P, D'Silva P.; ''Role of Magmas in protein transport and human mitochondria biogenesis.''; PubMed Europe PMC Scholia
44. Daithankar VN, Schaefer SA, Dong M, Bahnson BJ, Thorpe C.; ''Structure of the human sulfhydryl oxidase augmenter of liver regeneration and characterization of a human mutation causing an autosomal recessive myopathy .''; PubMed Europe PMC Scholia
45. Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N.; ''Multiple pathways for sorting mitochondrial precursor proteins.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
4xHC-TIMM10 [mitochondrial inner membrane]	Protein	P62072 (Uniprot-TrEMBL)
4xHC-TIMM10B [mitochondrial inner membrane]	Protein	Q9Y5J6 (Uniprot-TrEMBL)
4xHC-TIMM10B	Protein	Q9Y5J6 (Uniprot-TrEMBL)
4xHC-TIMM13 [mitochondrial intermembrane space]	Protein	Q9Y5L4 (Uniprot-TrEMBL)
4xHC-TIMM8A [mitochondrial intermembrane space]	Protein	O60220 (Uniprot-TrEMBL)
4xHC-TIMM8B(2-83) [mitochondrial intermembrane space]	Protein	Q9Y5J9 (Uniprot-TrEMBL)
4xHC-TIMM9(2-89) [mitochondrial inner membrane]	Protein	Q9Y5J7 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
CHCHD4 [mitochondrial intermembrane space]	Protein	Q8N4Q1 (Uniprot-TrEMBL)
Cargo of SAM50	Protein	REACT_118988 (Reactome)
Cargo of SAM50	Protein	REACT_119573 (Reactome)
Cargo of TIMM22	Protein	REACT_119317 (Reactome)
Cargo of TIMM22	Protein	REACT_119704 (Reactome)
Cargo of TIMM23 PAM	Protein	REACT_119139 (Reactome)
Cargo of TIMM23 SORT	Protein	REACT_119476 (Reactome)
Cargo of TOMM40	Protein	REACT_119170 (Reactome)
Cargo of TOMM40	Protein	REACT_119520 (Reactome)
DNAJC19 [mitochondrial inner membrane]	Protein	Q96DA6 (Uniprot-TrEMBL)
GFER [mitochondrial intermembrane space]	Protein	P55789 (Uniprot-TrEMBL)
GRPEL1 [mitochondrial inner membrane]	Protein	Q9HAV7 (Uniprot-TrEMBL)
GRPEL2 [mitochondrial inner membrane]	Protein	Q8TAA5 (Uniprot-TrEMBL)
HSPA9 [mitochondrial inner membrane]	Protein	P38646 (Uniprot-TrEMBL)
MIA40:ERV1	Complex	REACT_119823 (Reactome)
MTX1 [mitochondrial outer membrane]	Protein	Q13505 (Uniprot-TrEMBL)
MTX2 [mitochondrial outer membrane]	Protein	O75431 (Uniprot-TrEMBL)
Mitochondrial processing peptidase	Complex	REACT_119809 (Reactome)
PAM16 [mitochondrial inner membrane]	Protein	Q9Y3D7 (Uniprot-TrEMBL)
PMPCA [mitochondrial matrix]	Protein	Q10713 (Uniprot-TrEMBL)
PMPCB [mitochondrial matrix]	Protein	O75439 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
Precursor Cargo of TIMM23 PAM	Protein	REACT_119158 (Reactome)
Precursor Cargo of TIMM23 SORT	Protein	REACT_118927 (Reactome)
Products of MIA40:ERV1	Protein	REACT_119222 (Reactome)
Proteins Chaperoned by TIMM8:TIMM13	Protein	REACT_119274 (Reactome)
Proteins Chaperoned by TIMM9:TIMM10	Protein	REACT_119695 (Reactome)
SAM50 Complex	Complex	REACT_120017 (Reactome)	The SAM50 complex (SAMM50 complex) is inferred from homologous subunits in Saccharomyces cerevisiae. Xie et al. (2007) found human SAM50 in a complex with metaxin 1, metaxin 2, mitofilin, CHCHD3, CHCHD6, and DnaJC1 however Kozjak-Pavlovic et al. (2007) found SAM50 in a separate complex from the metaxins.
SAMM50 [mitochondrial outer membrane]	Protein	Q9Y512 (Uniprot-TrEMBL)
Substrates of MIA40:ERV1	Protein	REACT_119002 (Reactome)
TIMM17A [mitochondrial inner membrane]	Protein	Q99595 (Uniprot-TrEMBL)
TIMM17B [mitochondrial inner membrane]	Protein	O60830 (Uniprot-TrEMBL)
TIMM21 [mitochondrial inner membrane]	Protein	Q9BVV7 (Uniprot-TrEMBL)
TIMM22 [mitochondrial inner membrane]	Protein	Q9Y584 (Uniprot-TrEMBL)
TIMM22	Protein	Q9Y584 (Uniprot-TrEMBL)
TIMM23 SORT:Precursor Cargo	Complex	REACT_120218 (Reactome)
TIMM23 [mitochondrial inner membrane]	Protein	O14925 (Uniprot-TrEMBL)
TIMM23 Complex	Complex	REACT_119853 (Reactome)
TIMM23 PAM:Cargo	Complex	REACT_120146 (Reactome)
TIMM23 PAM:Precursor Cargo	Complex	REACT_118867 (Reactome)
TIMM23 SORT:Cargo	Complex	REACT_119235 (Reactome)
TIMM44(?-452) [mitochondrial inner membrane]	Protein	O43615 (Uniprot-TrEMBL)
TIMM50 [mitochondrial inner membrane]	Protein	Q3ZCQ8 (Uniprot-TrEMBL)
TIMM8:TIMM13:Protein	Complex	REACT_119483 (Reactome)
TIMM8:TIMM13	Complex	REACT_119612 (Reactome)
TIMM9:TIMM10:FXC1:TIM22:Protein	Complex	REACT_119578 (Reactome)
TIMM9:TIMM10:Protein	Complex	REACT_119702 (Reactome)
TIMM9:TIMM10	Complex	REACT_118963 (Reactome)
TOMM20 [mitochondrial outer membrane]	Protein	Q15388 (Uniprot-TrEMBL)
TOMM22 [mitochondrial outer membrane]	Protein	Q9NS69 (Uniprot-TrEMBL)
TOMM40 [mitochondrial outer membrane]	Protein	O96008 (Uniprot-TrEMBL)
TOMM40 Complex	Complex	REACT_120217 (Reactome)
TOMM5 [mitochondrial outer membrane]	Protein	Q8N4H5 (Uniprot-TrEMBL)
TOMM6 [mitochondrial outer membrane]	Protein	Q96B49 (Uniprot-TrEMBL)
TOMM7 [mitochondrial outer membrane]	Protein	Q9P0U1 (Uniprot-TrEMBL)
TOMM70A(2-608) [mitochondrial outer membrane]	Protein	O94826 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
4xHC-TIMM10B			REACT_118697 (Reactome)
	ADP	Arrow	REACT_118696 (Reactome)
ATP			REACT_118696 (Reactome)
	Cargo of SAM50	Arrow	REACT_118792 (Reactome)
Cargo of SAM50			REACT_118792 (Reactome)
	Cargo of TIMM22	Arrow	REACT_118820 (Reactome)
Cargo of TIMM22			REACT_118820 (Reactome)
	Cargo of TIMM23 PAM	Arrow	REACT_118696 (Reactome)
	Cargo of TIMM23 SORT	Arrow	REACT_118571 (Reactome)
	Cargo of TOMM40	Arrow	REACT_118675 (Reactome)
Cargo of TOMM40			REACT_118675 (Reactome)
MIA40:ERV1		mim-catalysis	REACT_118849 (Reactome)
Mitochondrial processing peptidase		mim-catalysis	REACT_118803 (Reactome)
Mitochondrial processing peptidase		mim-catalysis	REACT_118813 (Reactome)
	Pi	Arrow	REACT_118696 (Reactome)
Precursor Cargo of TIMM23 PAM			REACT_118832 (Reactome)
Precursor Cargo of TIMM23 SORT			REACT_118623 (Reactome)
	Products of MIA40:ERV1	Arrow	REACT_118849 (Reactome)
Proteins Chaperoned by TIMM8:TIMM13			REACT_118838 (Reactome)
Proteins Chaperoned by TIMM9:TIMM10			REACT_118732 (Reactome)
			REACT_118571 (Reactome)	As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the inner membrane. The presequences of proteins targeted to the inner membrane are transferred to the matrix where they are cleaved. Sequences in the mature regions of the proteins then interact with the TIMM23 complex to halt transfer across the inner membrane and the proteins are released laterally into the inner membrane. TIMM21 is required. In yeast experimentally verified substrates of the TIM23 complex targeted to the inner membrane include CYB2, DLD (LDHD in human), ATP9 (ATP5G1 in human), COQ2, TIM54 (TIMM54 in human), COX4, COX5A, and ATP2 (ATP5B in human). Many other inner membrane proteins are believed to be substrates of the TIMM23 complex.
			REACT_118623 (Reactome)	As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the inner membrane. The TIMM23 complex appears to adopt different configurations (and perhaps different subunit compositions) depending on whether the substrate is destined for the inner membrane or the matrix. Here we refer to the TIMM23 SORT complex as the configuration that delivers inner membrane proteins. The TIMM21 subunit is required for this activity. In yeast, the N-terminal presequences of precursors first interact with TIM50 and TIM23 (TIMM50 and TIMM23 in human). The TIM17 and TIM23 subunits (TIMM17 and TIMM23 in human) form a channel and are required to initiate translocation of precursors. In yeast experimentally verified substrates of the TIM23 SORT complex targeted to the inner membrane include CYB2, DLD (LDHD in human), ATP9 (ATP5G1 in human), COQ2, TIM54 (TIMM54 in human), COX4, COX5A, and ATP2 (ATP5B in human). Many other inner membrane proteins are believed to be substrates of the TIMM23 complex.
			REACT_118675 (Reactome)	As inferred from the yeast TOM40:TOM70 complex, the human TOMM40:TOMM70 complex transports precursor proteins from the cytosol, across the outer membrane of the mitochondrion, and into the intermembrane space from where they may be targeted to all locations within the mitochondrion. As inferred from yeast, TOMM40, TOMM22, TOMM5, TOMM6, and TOMM7 probably form the general import pore across the membrane. On the cytosolic side TOMM20 and TOMM22 interact with presequences on mitochondrial precursors while TOMM70 interacts with hydrophobic sequences in mature internal regions of mitochondrial proteins. In yeast, experimentally verified substrates of the TOM40:TOM70 complex include ATP1 (ATP5A1 in human), ATP2 (ATP5B in human), ATP9 (ATP5G1 in human), TOM40 (TOMM40 in human), SSC1 (mtHsp70, HSPA9 in human), CIT1 (CS in human), ACO1 (ACO2 in human), IDH1 (IDH3G in human), BCS1 (BCS1L in human), CYT1 (CYC1 in human), TIM54 (TIMM54 in human), TIM22 (TIMM22 in human), AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), HSP60, and CYB2. In humans, TOMM40 has been shown to be a substrate (Humphries et al. 2005). In yeast some proteins such as ACO1, ATP1, CIT1, IDH1, and ATP2 contain both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009). Most proteins imported into mitochondria are anticipated to be transported through the TOMM40:TOMM70 complex.
			REACT_118696 (Reactome)	As inferred from the yeast TIM23 complex, the human TIMM23 complex transports precursor proteins across the inner membrane and into the matrix. As in yeast, subunits TIMM50, TIMM17, and TIMM23 are probably necessary for initiating translocation while the PAM complex with mtHSP70 (HSPA9, yeast SSC1) provides the motive force that drives the transport. mtHSP70 binding to the precursor pulls the protein into the matrix in a reaction requiring ATP hydrolysis. The yeast reaction appears to use a Brownian ratchet mechanism (Yamano et al. 2008). In yeast experimentally verified substrates of TIM23 PAM include Hsp60 (HSP60 in human) and Yfh1 (Frataxin, FXN in human). Many other matrix proteins are believed to be substrates of the TIMM23 complex
			REACT_118697 (Reactome)	TIMM9:TIMM10 with bound substrate protein interacts with FXC1 (TIMM9B, TIMM10B) and TIMM22 at the inner membrane (Muhlenbein et al. 2004). It is believed that TIMM22 then inserts the protein into the inner membrane and TIMM9:TIMM10 and FXC1 are released.
			REACT_118732 (Reactome)	As inferred from the yeast TIM9:TIM10 complex, the human TIMM9:TIMM10:FXC1 complex chaperones hydrophobic membrane proteins in the intermembrane space until their insertion into the inner or outer membrane. Whereas the yeast TIM9:TIM10 complex is soluble in the intermembrane space, the human TIMM9:TIMM10 complex is associated with the outer surface of the inner membrane (Muhlebein et al. 2004). Experimentally verified substrates of the yeast TIM9:TIM10 complex include AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), TIM17 (TIMM17 in human), TOM40 (TOMM40 in human), TIM23 (TIMM23 in human), TIM22 (TIMM22 in human), and Tafazzin (Tafazzin, TAZ in human). Many other mitochondrial proteins are anticipated to be chaperoned by the TIMM9:TIMM10 complex.
			REACT_118792 (Reactome)	As inferred from the yeast SAM50 complex, the human SAMM50 Complex (SAM50 complex, TOB55 complex) inserts mainly beta-barrel proteins into the outer membrane after they have passed from the cytosol, through the TOMM40:TOMM70 complex, and into the intermembrane space. In yeast, experimentally verified substrates of the SAM50 complex include TOM40 (TOMM40 in human), MDM10, Porin1 (VDAC1 in human), and TOM22 (TOMM22 in human). In humans, TOMM40 (Humphries et al. 2005) and VDAC1 (Kozjak-Pavlovic et al. 2007, homologous to yeast Porin1) have been shown to be substrates. Many other mitochondrial proteins are anticipated to be substrates of the SAMM50 complex.
			REACT_118803 (Reactome)	As inferred from yeast, the alpha subunit of the mitochondrial processing peptidase (MPP) binds presequences of mitochondrial precursors and the beta subunit cleaves the presequence. After cleavage, proteins destined for the matrix are drawn into the matrix by ATP-dependent interaction with mtHSP70 (HSPA9, homolog of yeast SSC1) of the PAM complex.
			REACT_118813 (Reactome)	As inferred from yeast, the alpha subunit of the mitochondrial processing peptidase (MPP) binds presequences of mitochondrial precursors and the beta subunit cleaves the presequence. After cleavage, proteins destined for the inner membrane are released laterally from TIMM23 SORT into the membrane.
			REACT_118820 (Reactome)	As inferred from the yeast TIM22 complex, human TIMM22 inserts precursor proteins into the inner membrane of the mitochondrion. The precursors are hydrophobic and may be chaperoned to TIMM22 by small TIM proteins (TIMM10, TIMM12) of the intermembrane space. In yeast, experimentally verified substrates of the TIM22 complex include AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), PIC, TIM22 (TIMM22 in human), and TIM23 (TIMM23 in human). Many other inner membrane proteins are anticipated to be substrates ofthe TIMM22 complex.
			REACT_118832 (Reactome)	As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the matrix. The TIMM23 complex appears to adopt different configurations (and perhaps different subunit compositions) depending on whether the substrate is destined for the inner membrane or the matrix. Here we refer to the TIMM23 PAM complex as the configuration that delivers inner membrane proteins. The PAM17 subcomplex is required for this activity. The N-terminal presequence of precursors first interacts with TIMM50 and TIMM23. The TIMM17 and TIMM23 subunits form a channel and are required to initiate translocation of precursors. In yeast experimentally verified substrates of TIM23:PAM include Hsp60 (HSP60 in human) and Yfh1 (Frataxin, FXN in human). Many other matrix proteins are believed to be substrates of the TIMM23 complex.
			REACT_118838 (Reactome)	As inferred from the yeast TIM8:TIM13 complex, the human TIMM8:TIMM13 complex chaperones hydrophobic membrane proteins in the intermembrane space until their insertion into the inner or outer membrane. In yeast experimentally verified substrates of the TIM8:TIM13 complex include TIM23 (TIMM23 in human) and TOM40 (TOMM40 in human). Many other mitochondrial proteins are anticipated to be chaperoned by the TIMM8:TIMM13 complex.
			REACT_118849 (Reactome)	As inferred from the yeast MIA40:ERV1 complex, human CHCHD4 (MIA40 homolog) catalyzes the oxidation of cysteine residues in precursor proteins in the intermembrane space to form cystine bonds. The electrons from the cysteine residues are transferred to CHCHD4, then to GFER (ERV1 homolog), and eventually to the respiratory chain. The interaction between yeast MIA40 and ERV1 is transitory. In yeast, experimentally verified substrates of MIA40:ERV1 include COX17, COX19, CMC2, CMC3, CMC4, TIM13 (TIMM13 in human), TIM9 (TIMM9 in human), TIM10 (TIMM10 in human), CCS1 (CCS in human), TIM8 (TIMM8 in human), and ERV1 (GFER in human). Many other mitochondrial proteins are anticipated to be substrates of the MIA40:ERV1 complex.
SAM50 Complex		mim-catalysis	REACT_118792 (Reactome)
Substrates of MIA40:ERV1			REACT_118849 (Reactome)
TIMM22			REACT_118697 (Reactome)
TIMM22		mim-catalysis	REACT_118820 (Reactome)
	TIMM23 SORT:Precursor Cargo	Arrow	REACT_118623 (Reactome)
TIMM23 SORT:Precursor Cargo			REACT_118813 (Reactome)
	TIMM23 Complex	Arrow	REACT_118571 (Reactome)
	TIMM23 Complex	Arrow	REACT_118696 (Reactome)
TIMM23 Complex			REACT_118623 (Reactome)
TIMM23 Complex			REACT_118832 (Reactome)
	TIMM23 PAM:Cargo	Arrow	REACT_118803 (Reactome)
TIMM23 PAM:Cargo			REACT_118696 (Reactome)
TIMM23 PAM:Cargo		mim-catalysis	REACT_118696 (Reactome)
	TIMM23 PAM:Precursor Cargo	Arrow	REACT_118832 (Reactome)
TIMM23 PAM:Precursor Cargo			REACT_118803 (Reactome)
	TIMM23 SORT:Cargo	Arrow	REACT_118813 (Reactome)
TIMM23 SORT:Cargo			REACT_118571 (Reactome)
TIMM23 SORT:Cargo		mim-catalysis	REACT_118571 (Reactome)
	TIMM8:TIMM13:Protein	Arrow	REACT_118838 (Reactome)
TIMM8:TIMM13			REACT_118838 (Reactome)
	TIMM9:TIMM10:FXC1:TIM22:Protein	Arrow	REACT_118697 (Reactome)
	TIMM9:TIMM10:Protein	Arrow	REACT_118732 (Reactome)
TIMM9:TIMM10:Protein			REACT_118697 (Reactome)
TIMM9:TIMM10			REACT_118732 (Reactome)
TOMM40 Complex		mim-catalysis	REACT_118675 (Reactome)