Mitochondrial protein import (Homo sapiens)

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2, 3, 5, 7, 22...7, 437, 11, 437, 32, 437, 28, 437, 28, 431, 7, 18, 19, 21...7, 8, 43, 447, 437, 437, 8, 22, 437, 437, 32, 439, 12, 15, 24, 407, 35, 43mitochondrial intermembrane spacecytosolmitochondrial matrixGRPEL2 Precursor Cargo ofTIMM23 SORTHSCB GRPEL2 Cargo of SAM50VDAC1 TIMM23 PAM:PrecursorCargoTOMM40 ComplexCHCHD10 SLC25A12 TIMM50 MTX1 OTC(1-32) VDAC1 4xHC-TIMM8A MTX2 Mitochondrial targeting peptides (from matrix proteins) GRPEL2 TOMM22 ATP5B(1-529) 4xHC-TIMM13 TIMM13 4xHC-TIMM10B CHCHD3 FXN(1-41) HSPA9 ATP5B 4xHC-CHCHD5 4xHC-COA4 4xHC-CHCHD7 TIMM17A PAM16 HSPD1(1-573) Products ofMIA40:ERV1BCS1L Cargo of TOMM40ATP5B TIMM8:TIMM13ATP5G1 HSCB DNAJC19 TIMM50 TIMM17A DNAJC19 SLC25A4 TIMM17B H2OTIMM17A TOMM20 Cargo of TIMM22SLC25A6 SLC25A4 TIMM23 FXN(42-210) H2O4xHC-TIMM8A PAM16 SAM complexATP5G1 TIMM50 DNAJC19 ACO2(1-780) COQ2 TIMM21 CHCHD2 4xHC-COX17 PAM16 TIMM23 TIMM23 ATP5B(1-529) COA6 MitochondrialprocessingpeptidaseSAMM50 CHCHD5 HSPD1 PAM16 DNAJC19 TIMM21 TOMM40 Substrates ofMIA40:ERV1TOMM40 ATP5B(1-529) COQ2(1-34) DNAJC19 HSPD1(1-573) GFER COX19 GRPEL1 Cargo of SAM50TOMM40 Precursor Cargo ofTIMM23 PAMPMPCB MIA40:ERV1TIMM23 4xHC-COA6 TIMM17B TIMM17B CMC4 4xHC-TIMM10 4xHC-TIMM10BDNAJC19 TIMM23 SORT:CargoTIMM9:TIMM10:TIMM10B:TIM22:ProteinFXN(1-210) TIMM23 ADPTIMM8:TIMM13:ProteinPITRM1Mitochondrialtargeting peptides(from innermembrane proteins)ATP5B(1-529) SLC25A4 Cargo of TIMM22PAM16 HSPA9 TIMM17B FXN(1-210) TIMM23 Complex4xHC-TIMM9 HSPA9 TOMM6 TIMM17B COA4 SLC25A13 SLC25A4 4xHC-TIMM10 GRPEL2 TIMM50 LDHD(1-507) ATP5G1(1-136) TIMM22 TIMM21 GRPEL1 ATP5G1(1-136) 4xHC-TIMM9 TOMM40 TIMM17B TIMM22 TIMM21 TIMM22 LDHD(1-507) ATP5G1(1-136) Proteins Chaperonedby TIMM9:TIMM10Cargo of TOMM40SLC25A4 BCS1L TIMM44(?-452) TIMM17A SLC25A13 TIMM21 TIMM23 Complex4xHC-TIMM8A 4xHC-CHCHD10 TIMM17B HSPA9 TIMM21 HSPA9 TIMM50 TOMM7 HSCB(1-235) OTC(1-354) CHCHD7 TOMM40 COQ2(1-371) TIMM44(?-452) GRPEL2 HSCB(1-30) ACO2(1-780) SLC25A6 HSPD1(1-573) TIMM23 PAM16 TIMM22 TAZ HSPD1 ATP5A1(1-553) TIMM9:TIMM10:ProteinTIMM17A TIMM17A NDUFB8(1-28) ATP5A1(1-553) 4xHC-TIMM8B COX17 TIMM22 TIMM44(?-452) PiNDUFB8(1-186) TIMM23SORT:PrecursorCargoNDUFB8(1-186) LDHD(?-507) TIMM23 PAM:Cargo4xHC-TIMM13 TOMM70A TIMM17A COQ2(1-371) TIMM23 HSPD1(1-573) TOMM40 FXN(42-210) TIMM23 Mitochondrial targeting peptides (from inner membrane proteins) TIMM22 LDHD(1-?) TIMM44(?-452) GRPEL1 HSPA9(1-679) CMC2 4xHC-TIMM13 Mitochondrialtargeting peptidesTIMM17B HSCB(1-235) CYC1(1-325) HSPA9(1-679) TIMM8B NDUFB8 4xHC-TIMM9 SLC25A6 TIMM44(?-452) TIMM17B 4xHC-TIMM8B LDHD(?-507) TIMM17A COQ2 4xHC-CMC2 CS(1-466) 4xHC-CHCHD3 TIMM23 SLC25A4 PMPCA NDUFB8 CHCHD4 TIMM9:TIMM10GRPEL1 HSPA9 TIMM22ATP5G1(1-136) GRPEL1 CS(1-466) OTC(1-354) TIMM23 TOMM5 Cargo of TIMM23 PAMHSPD1(1-26) TIMM23 ATP5G1(1-61) ATPATP5B(1-47) TAZ GRPEL2 4xHC-TIMM8B Mitochondrialtargeting peptides(from matrixproteins)TIMM22 IDH3G(1-393) TOMM40 TIMM8A TAZ IDH3G(1-393) TIMM17A TIMM23 SLC25A4 Proteins Chaperonedby TIMM8:TIMM13OTC SLC25A12 4xHC-TIMM10 TIMM50 TIMM23 Cargo of TIMM23 SORTGRPEL1 TIMM44(?-452) 6xHC-CMC4 2xHC-CHCHD2 4xHC-COX19 CYC1(1-325) OTC 374, 426, 31, 38133714132810, 4416, 34373513133019, 20, 4537166, 31, 3816201637372519, 414515, 401416, 3416, 3416, 343016, 3419, 414516, 344, 422816, 34202817


Description

A human mitochondrion contains about 1500 proteins, more than 99% of which are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondrion. Proteins are targeted to four locations (outer membrane, intermembrane space, inner membrane, and matrix) and must be sorted accordingly (reviewed in Kutik et al. 2007, Milenkovic et al. 2007, Bolender et al. 2008, Endo and Yamano 2009, Wiedemann and Pfanner 2017, Kang et al. 2018). Newly synthesized proteins are transported from the cytosol across the outer membrane by the TOMM40:TOMM70 complex. Proteins that contain presequences first interact with the TOMM20 subunit of the complex while proteins that contain internal targeting elements first interact with the TOMM70 subunit. After initial interaction the protein is conducted across the outer membrane by TOMM40 subunits. In yeast some proteins such as Aco1, Atp1, Cit1, Idh1, and Atp2 have both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009).
After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1268020
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
101498view11:36, 1 November 2018ReactomeTeamreactome version 66
101035view21:17, 31 October 2018ReactomeTeamreactome version 65
100568view19:51, 31 October 2018ReactomeTeamreactome version 64
100117view16:36, 31 October 2018ReactomeTeamreactome version 63
99667view15:06, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99265view12:45, 31 October 2018ReactomeTeamreactome version 62
93923view13:45, 16 August 2017ReactomeTeamreactome version 61
93502view11:25, 9 August 2017ReactomeTeamreactome version 61
87961view13:12, 25 July 2016RyanmillerOntology Term : 'peptide and protein metabolic process' added !
87957view13:11, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86597view09:21, 11 July 2016ReactomeTeamreactome version 56
83322view10:46, 18 November 2015ReactomeTeamVersion54
81760view10:04, 26 August 2015ReactomeTeamVersion53
76934view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76639view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
75969view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75672view10:58, 10 June 2014ReactomeTeamReactome 48 Update
75027view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74671view08:44, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHC-CHCHD2 ProteinQ9Y6H1 (Uniprot-TrEMBL)
4xHC-CHCHD10 ProteinQ8WYQ3 (Uniprot-TrEMBL)
4xHC-CHCHD3 ProteinQ9NX63 (Uniprot-TrEMBL)
4xHC-CHCHD5 ProteinQ9BSY4 (Uniprot-TrEMBL)
4xHC-CHCHD7 ProteinQ9BUK0 (Uniprot-TrEMBL)
4xHC-CMC2 ProteinQ9NRP2 (Uniprot-TrEMBL)
4xHC-COA4 ProteinQ9NYJ1 (Uniprot-TrEMBL)
4xHC-COA6 ProteinQ5JTJ3 (Uniprot-TrEMBL)
4xHC-COX17 ProteinQ14061 (Uniprot-TrEMBL)
4xHC-COX19 ProteinQ49B96 (Uniprot-TrEMBL)
4xHC-TIMM10 ProteinP62072 (Uniprot-TrEMBL)
4xHC-TIMM10B ProteinQ9Y5J6 (Uniprot-TrEMBL)
4xHC-TIMM10BProteinQ9Y5J6 (Uniprot-TrEMBL)
4xHC-TIMM13 ProteinQ9Y5L4 (Uniprot-TrEMBL)
4xHC-TIMM8A ProteinO60220 (Uniprot-TrEMBL)
4xHC-TIMM8B ProteinQ9Y5J9 (Uniprot-TrEMBL)
4xHC-TIMM9 ProteinQ9Y5J7 (Uniprot-TrEMBL)
6xHC-CMC4 ProteinP56277 (Uniprot-TrEMBL)
ACO2(1-780) ProteinQ99798 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATP5A1(1-553) ProteinP25705 (Uniprot-TrEMBL)
ATP5B ProteinP06576 (Uniprot-TrEMBL)
ATP5B(1-47) ProteinP06576 (Uniprot-TrEMBL)
ATP5B(1-529) ProteinP06576 (Uniprot-TrEMBL)
ATP5G1 ProteinP05496 (Uniprot-TrEMBL)
ATP5G1(1-136) ProteinP05496 (Uniprot-TrEMBL)
ATP5G1(1-61) ProteinP05496 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BCS1L ProteinQ9Y276 (Uniprot-TrEMBL)
CHCHD10 ProteinQ8WYQ3 (Uniprot-TrEMBL)
CHCHD2 ProteinQ9Y6H1 (Uniprot-TrEMBL)
CHCHD3 ProteinQ9NX63 (Uniprot-TrEMBL)
CHCHD4 ProteinQ8N4Q1 (Uniprot-TrEMBL)
CHCHD5 ProteinQ9BSY4 (Uniprot-TrEMBL)
CHCHD7 ProteinQ9BUK0 (Uniprot-TrEMBL)
CMC2 ProteinQ9NRP2 (Uniprot-TrEMBL)
CMC4 ProteinP56277 (Uniprot-TrEMBL)
COA4 ProteinQ9NYJ1 (Uniprot-TrEMBL)
COA6 ProteinQ5JTJ3 (Uniprot-TrEMBL)
COQ2 ProteinQ96H96 (Uniprot-TrEMBL)
COQ2(1-34) ProteinQ96H96 (Uniprot-TrEMBL)
COQ2(1-371) ProteinQ96H96 (Uniprot-TrEMBL)
COX17 ProteinQ14061 (Uniprot-TrEMBL)
COX19 ProteinQ49B96 (Uniprot-TrEMBL)
CS(1-466) ProteinO75390 (Uniprot-TrEMBL)
CYC1(1-325) ProteinP08574 (Uniprot-TrEMBL)
Cargo of SAM50ComplexR-HSA-1268003 (Reactome)
Cargo of SAM50ComplexR-HSA-1268005 (Reactome)
Cargo of TIMM22ComplexR-HSA-1307796 (Reactome)
Cargo of TIMM22ComplexR-HSA-1307800 (Reactome)
Cargo of TIMM23 PAMComplexR-HSA-1299460 (Reactome)
Cargo of TIMM23 SORTComplexR-HSA-1299464 (Reactome)
Cargo of TOMM40ComplexR-HSA-1268006 (Reactome)
Cargo of TOMM40ComplexR-HSA-1268010 (Reactome)
DNAJC19 ProteinQ96DA6 (Uniprot-TrEMBL)
FXN(1-210) ProteinQ16595 (Uniprot-TrEMBL)
FXN(1-41) ProteinQ16595 (Uniprot-TrEMBL)
FXN(42-210) ProteinQ16595 (Uniprot-TrEMBL)
GFER ProteinP55789 (Uniprot-TrEMBL)
GRPEL1 ProteinQ9HAV7 (Uniprot-TrEMBL)
GRPEL2 ProteinQ8TAA5 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HSCB ProteinQ8IWL3 (Uniprot-TrEMBL)
HSCB(1-235) ProteinQ8IWL3 (Uniprot-TrEMBL)
HSCB(1-30) ProteinQ8IWL3 (Uniprot-TrEMBL)
HSPA9 ProteinP38646 (Uniprot-TrEMBL)
HSPA9(1-679) ProteinP38646 (Uniprot-TrEMBL)
HSPD1 ProteinP10809 (Uniprot-TrEMBL)
HSPD1(1-26) ProteinP10809 (Uniprot-TrEMBL)
HSPD1(1-573) ProteinP10809 (Uniprot-TrEMBL)
IDH3G(1-393) ProteinP51553 (Uniprot-TrEMBL)
LDHD(1-507) ProteinQ86WU2 (Uniprot-TrEMBL)
LDHD(1-?) ProteinQ86WU2 (Uniprot-TrEMBL)
LDHD(?-507) ProteinQ86WU2 (Uniprot-TrEMBL) The N-terminus of LDLD is predicted by software.
MIA40:ERV1ComplexR-HSA-1307797 (Reactome)
MTX1 ProteinQ13505 (Uniprot-TrEMBL)
MTX2 ProteinO75431 (Uniprot-TrEMBL)
Mitochondrial

processing

peptidase
ComplexR-HSA-1299458 (Reactome)
Mitochondrial

targeting peptides (from inner

membrane proteins)
ComplexR-HSA-8986177 (Reactome)
Mitochondrial

targeting peptides (from matrix

proteins)
ComplexR-HSA-8986114 (Reactome)
Mitochondrial targeting peptidesComplexR-HSA-8986144 (Reactome)
Mitochondrial targeting peptides (from inner membrane proteins) R-HSA-8986177 (Reactome)
Mitochondrial targeting peptides (from matrix proteins) R-HSA-8986114 (Reactome)
NDUFB8 ProteinO95169 (Uniprot-TrEMBL)
NDUFB8(1-186) ProteinO95169 (Uniprot-TrEMBL)
NDUFB8(1-28) ProteinO95169 (Uniprot-TrEMBL)
OTC ProteinP00480 (Uniprot-TrEMBL)
OTC(1-32) ProteinP00480 (Uniprot-TrEMBL)
OTC(1-354) ProteinP00480 (Uniprot-TrEMBL)
PAM16 ProteinQ9Y3D7 (Uniprot-TrEMBL)
PITRM1ProteinQ5JRX3 (Uniprot-TrEMBL)
PMPCA ProteinQ10713 (Uniprot-TrEMBL)
PMPCB ProteinO75439 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
Precursor Cargo of TIMM23 PAMComplexR-HSA-1299468 (Reactome)
Precursor Cargo of TIMM23 SORTComplexR-HSA-1268004 (Reactome)
Products of MIA40:ERV1ComplexR-HSA-1307799 (Reactome)
Proteins Chaperoned by TIMM8:TIMM13ComplexR-HSA-1299467 (Reactome)
Proteins Chaperoned by TIMM9:TIMM10ComplexR-HSA-1955378 (Reactome)
SAM complexComplexR-HSA-1252247 (Reactome) The SAM 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 ProteinQ9Y512 (Uniprot-TrEMBL)
SLC25A12 ProteinO75746 (Uniprot-TrEMBL)
SLC25A13 ProteinQ9UJS0 (Uniprot-TrEMBL)
SLC25A4 ProteinP12235 (Uniprot-TrEMBL)
SLC25A6 ProteinP12236 (Uniprot-TrEMBL)
Substrates of MIA40:ERV1ComplexR-HSA-1307798 (Reactome)
TAZ ProteinQ16635 (Uniprot-TrEMBL)
TIMM13 ProteinQ9Y5L4 (Uniprot-TrEMBL)
TIMM17A ProteinQ99595 (Uniprot-TrEMBL)
TIMM17B ProteinO60830 (Uniprot-TrEMBL)
TIMM21 ProteinQ9BVV7 (Uniprot-TrEMBL)
TIMM22 ProteinQ9Y584 (Uniprot-TrEMBL)
TIMM22ProteinQ9Y584 (Uniprot-TrEMBL)
TIMM23

SORT:Precursor

Cargo
ComplexR-HSA-1299473 (Reactome)
TIMM23 ComplexComplexR-HSA-1252242 (Reactome)
TIMM23 ProteinO14925 (Uniprot-TrEMBL)
TIMM23 PAM:CargoComplexR-HSA-1299474 (Reactome)
TIMM23 PAM:Precursor CargoComplexR-HSA-1299462 (Reactome)
TIMM23 SORT:CargoComplexR-HSA-1299469 (Reactome)
TIMM44(?-452) ProteinO43615 (Uniprot-TrEMBL)
TIMM50 ProteinQ3ZCQ8 (Uniprot-TrEMBL)
TIMM8:TIMM13:ProteinComplexR-HSA-1299471 (Reactome)
TIMM8:TIMM13ComplexR-HSA-1299461 (Reactome)
TIMM8A ProteinO60220 (Uniprot-TrEMBL)
TIMM8B ProteinQ9Y5J9 (Uniprot-TrEMBL)
TIMM9:TIMM10:ProteinComplexR-HSA-1955377 (Reactome)
TIMM9:TIMM10:TIMM10B:TIM22:ProteinComplexR-HSA-1299470 (Reactome)
TIMM9:TIMM10ComplexR-HSA-1955372 (Reactome)
TOMM20 ProteinQ15388 (Uniprot-TrEMBL)
TOMM22 ProteinQ9NS69 (Uniprot-TrEMBL)
TOMM40 ComplexComplexR-HSA-1252240 (Reactome)
TOMM40 ProteinO96008 (Uniprot-TrEMBL)
TOMM5 ProteinQ8N4H5 (Uniprot-TrEMBL)
TOMM6 ProteinQ96B49 (Uniprot-TrEMBL)
TOMM7 ProteinQ9P0U1 (Uniprot-TrEMBL)
TOMM70A ProteinO94826 (Uniprot-TrEMBL)
VDAC1 ProteinP21796 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
4xHC-TIMM10BR-HSA-1955380 (Reactome)
ADPArrowR-HSA-1299475 (Reactome)
ATPR-HSA-1299475 (Reactome)
Cargo of SAM50ArrowR-HSA-1268025 (Reactome)
Cargo of SAM50R-HSA-1268025 (Reactome)
Cargo of TIMM22ArrowR-HSA-1307803 (Reactome)
Cargo of TIMM22R-HSA-1307803 (Reactome)
Cargo of TIMM23 PAMArrowR-HSA-1299475 (Reactome)
Cargo of TIMM23 SORTArrowR-HSA-1299482 (Reactome)
Cargo of TOMM40ArrowR-HSA-1268022 (Reactome)
Cargo of TOMM40R-HSA-1268022 (Reactome)
H2OR-HSA-1299476 (Reactome)
H2OR-HSA-1299478 (Reactome)
MIA40:ERV1mim-catalysisR-HSA-1307802 (Reactome)
Mitochondrial

processing

peptidase
mim-catalysisR-HSA-1299476 (Reactome)
Mitochondrial

processing

peptidase
mim-catalysisR-HSA-1299478 (Reactome)
Mitochondrial

targeting peptides (from inner

membrane proteins)
ArrowR-HSA-1299476 (Reactome)
Mitochondrial

targeting peptides (from matrix

proteins)
ArrowR-HSA-1299478 (Reactome)
Mitochondrial targeting peptidesR-HSA-8986181 (Reactome)
PITRM1mim-catalysisR-HSA-8986181 (Reactome)
PiArrowR-HSA-1299475 (Reactome)
Precursor Cargo of TIMM23 PAMR-HSA-1299480 (Reactome)
Precursor Cargo of TIMM23 SORTR-HSA-1299487 (Reactome)
Products of MIA40:ERV1ArrowR-HSA-1307802 (Reactome)
Proteins Chaperoned by TIMM8:TIMM13R-HSA-1299484 (Reactome)
Proteins Chaperoned by TIMM9:TIMM10R-HSA-1299481 (Reactome)
R-HSA-1268022 (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.
R-HSA-1268025 (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.
R-HSA-1299475 (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
R-HSA-1299476 (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.
R-HSA-1299478 (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.
R-HSA-1299480 (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 (Zhang et al. 2013). 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.
R-HSA-1299481 (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.
R-HSA-1299482 (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.
R-HSA-1299484 (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.
R-HSA-1299487 (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, Zhang et al. 2013). 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.
R-HSA-1307802 (Reactome) Proteins are imported into the intermembrane space via the interaction between cysteine residues on the imported protein and CHCHD4 (MIA40 in yeast), which functions as a receptor to mediate translocation across the outer membrane. 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 in yeast), 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.
R-HSA-1307803 (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.
R-HSA-1955380 (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.
R-HSA-8986181 (Reactome) After MPP cleaves off targeting peptides (also called presequences) of proteins imported into the mitochondrial matrix, PITRM1 (also called PreP) proteolyzes the cleaved targeting peptides (Pinho et al. 2010, Alikhani et al. 2011, Teixeira et al. 2012). PITRM1 also cleaves amyloid beta peptide that is imported into the matrix (Falkevall et al. 2006). Missense mutations in PITRM1 are associated with a neurological syndrome comprising mental retardation, spinocerebellar ataxia, cognitive decline, psychosis and possible epilepsy (Brunetti et al. 2016).
SAM complexmim-catalysisR-HSA-1268025 (Reactome)
Substrates of MIA40:ERV1R-HSA-1307802 (Reactome)
TIMM22R-HSA-1955380 (Reactome)
TIMM22mim-catalysisR-HSA-1307803 (Reactome)
TIMM23

SORT:Precursor

Cargo
ArrowR-HSA-1299487 (Reactome)
TIMM23

SORT:Precursor

Cargo
R-HSA-1299476 (Reactome)
TIMM23 ComplexArrowR-HSA-1299475 (Reactome)
TIMM23 ComplexArrowR-HSA-1299482 (Reactome)
TIMM23 ComplexR-HSA-1299480 (Reactome)
TIMM23 ComplexR-HSA-1299487 (Reactome)
TIMM23 PAM:CargoArrowR-HSA-1299478 (Reactome)
TIMM23 PAM:CargoR-HSA-1299475 (Reactome)
TIMM23 PAM:Cargomim-catalysisR-HSA-1299475 (Reactome)
TIMM23 PAM:Precursor CargoArrowR-HSA-1299480 (Reactome)
TIMM23 PAM:Precursor CargoR-HSA-1299478 (Reactome)
TIMM23 SORT:CargoArrowR-HSA-1299476 (Reactome)
TIMM23 SORT:CargoR-HSA-1299482 (Reactome)
TIMM23 SORT:Cargomim-catalysisR-HSA-1299482 (Reactome)
TIMM8:TIMM13:ProteinArrowR-HSA-1299484 (Reactome)
TIMM8:TIMM13R-HSA-1299484 (Reactome)
TIMM9:TIMM10:ProteinArrowR-HSA-1299481 (Reactome)
TIMM9:TIMM10:ProteinR-HSA-1955380 (Reactome)
TIMM9:TIMM10:TIMM10B:TIM22:ProteinArrowR-HSA-1955380 (Reactome)
TIMM9:TIMM10R-HSA-1299481 (Reactome)
TOMM40 Complexmim-catalysisR-HSA-1268022 (Reactome)
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