Mitochondrial protein import (Homo sapiens)

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4, 9-11, 13...11, 213, 11, 21, 2211, 2111, 19, 2111, 217, 11, 2111, 2111, 17, 2111, 215, 11, 12, 14, 15, 213, 8, 11, 2111, 217, 11, 21TIMM8TIMM13 TIMM23 Complex PAM Complex PAM Complex TIMM23 PAMCargo TIMM17 TIMM8BTIMM13 TIMM9TIMM10FXC1TIM22Protein TIMM17 TIMM9TIMM10FXC1 mitochondrial intermembrane spaceGRPEL1 or GRPEL2 TIMM17 TIMM8TIMM13Protein TIMM23 Complex PAM Complex PAM Complex GRPEL1 or GRPEL2 SAM50 Complex TIMM8BTIMM13 TIMM9TIMM10 TIMM8TIMM13 cytosolGRPEL1 or GRPEL2 TIMM9TIMM10 MIA40ERV1 TIMM23 PAMPrecursor Cargo GRPEL1 or GRPEL2 TIMM23 Complex TIMM17 GRPEL1 or GRPEL2 PAM Complex TIMM8ATIMM13 TIMM23 Complex TIMM17 TIMM9TIMM10Protein TOMM40 Complex Mitochondrial processing peptidase TIMM23 Complex TIMM23 SORTPrecursor Cargo mitochondrial matrixPAM Complex TIMM8ATIMM13 TIMM23 SORTCargo GRPEL1 or GRPEL2 TIMM23 Complex TIMM17 TIMM17A TIMM8TIMM13ProteinMTX1 TOMM7 TIMM22TIMM50 TIMM50 TIMM17B SAM50 ComplexTIMM23 Complex4xHC-TIMM9Proteins Chaperoned by TIMM8TIMM13GRPEL2 DNAJC19 4xHC-TIMM10BTIMM21 ATP4xHC-TIMM9TIMM44HSPA9 PiGRPEL2 TIMM50 4xHC-TIMM8A Cargo of SAM50TIMM17A HSPA9 PAM16 4xHC-TIMM13 MTX2 PAM16 TIMM23 TIMM44Cargo of TOMM40TIMM21 TIMM21 CHCHD4 TIMM23 SORTPrecursor CargoSubstrates of MIA40ERV1GRPEL1 PMPCA MIA40ERV1Cargo of TOMM40TIMM23 DNAJC19 4xHC-TIMM10B 4xHC-TIMM13 ADPTIMM44TIMM17B TIMM17A TIMM17B TIMM9TIMM10TIMM21 Mitochondrial processing peptidaseCargo of SAM50TIMM23 PAMCargoPrecursor Cargo of TIMM23 SORT4xHC-TIMM10 GRPEL2 GRPEL1 TIMM23 4xHC-TIMM8A TOMM40 HSPA9 TIMM23 TIMM23 PAMPrecursor CargoGRPEL1 TIMM44Cargo of TIMM22Cargo of TIMM23 SORTDNAJC19 DNAJC19 TIMM50 TOMM20 GFER TIMM23 SAMM50 TIMM21 DNAJC19 TIMM17B Cargo of TIMM22Products of MIA40ERV1GRPEL2 TIMM9TIMM10ProteinTOMM22 4xHC-TIMM10 TOMM5 4xHC-TIMM8BGRPEL2 4xHC-TIMM9TOMM70ATIMM8TIMM13TIMM17B TIMM17A Precursor Cargo of TIMM23 PAMTOMM6 TIMM50 PAM16 TIMM444xHC-TIMM8BTIMM9TIMM10FXC1TIM22ProteinGRPEL1 TIMM23 ComplexTIMM23 SORTCargoProteins Chaperoned by TIMM9TIMM10PAM16 4xHC-TIMM10 PMPCB DNAJC19 PAM16 HSPA9 HSPA9 TIMM44TOMM40 ComplexPAM16 TIMM23 TIMM21 GRPEL1 Cargo of TIMM23 PAMTIMM17A TIMM17B HSPA9 TIMM22 TIMM50 GRPEL2 GRPEL1 TIMM17A 117119716, 82, 20712, 201


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). 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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1268020

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114933view16:45, 25 January 2021ReactomeTeamReactome version 75
113378view11:45, 2 November 2020ReactomeTeamReactome version 74
112583view15:55, 9 October 2020ReactomeTeamReactome version 73
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

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NameTypeDatabase referenceComment
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-TIMM8BProteinQ9Y5J9 (Uniprot-TrEMBL)
4xHC-TIMM9ProteinQ9Y5J7 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CHCHD4 ProteinQ8N4Q1 (Uniprot-TrEMBL)
Cargo of SAM50ProteinREACT_118988 (Reactome)
Cargo of SAM50ProteinREACT_119573 (Reactome)
Cargo of TIMM22ProteinREACT_119317 (Reactome)
Cargo of TIMM22ProteinREACT_119704 (Reactome)
Cargo of TIMM23 PAMProteinREACT_119139 (Reactome)
Cargo of TIMM23 SORTProteinREACT_119476 (Reactome)
Cargo of TOMM40ProteinREACT_119170 (Reactome)
Cargo of TOMM40ProteinREACT_119520 (Reactome)
DNAJC19 ProteinQ96DA6 (Uniprot-TrEMBL)
GFER ProteinP55789 (Uniprot-TrEMBL)
GRPEL1 ProteinQ9HAV7 (Uniprot-TrEMBL)
GRPEL2 ProteinQ8TAA5 (Uniprot-TrEMBL)
HSPA9 ProteinP38646 (Uniprot-TrEMBL)
MIA40 ERV1ComplexREACT_119823 (Reactome)
MTX1 ProteinQ13505 (Uniprot-TrEMBL)
MTX2 ProteinO75431 (Uniprot-TrEMBL)
Mitochondrial processing peptidaseComplexREACT_119809 (Reactome)
PAM16 ProteinQ9Y3D7 (Uniprot-TrEMBL)
PMPCA ProteinQ10713 (Uniprot-TrEMBL)
PMPCB ProteinO75439 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
Precursor Cargo of TIMM23 PAMProteinREACT_119158 (Reactome)
Precursor Cargo of TIMM23 SORTProteinREACT_118927 (Reactome)
Products of MIA40 ERV1ProteinREACT_119222 (Reactome)
Proteins Chaperoned by TIMM8 TIMM13ProteinREACT_119274 (Reactome)
Proteins Chaperoned by TIMM9 TIMM10ProteinREACT_119695 (Reactome)
SAM50 ComplexComplexREACT_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 ProteinQ9Y512 (Uniprot-TrEMBL)
Substrates of MIA40 ERV1ProteinREACT_119002 (Reactome)
TIMM17A ProteinQ99595 (Uniprot-TrEMBL)
TIMM17B ProteinO60830 (Uniprot-TrEMBL)
TIMM21 ProteinQ9BVV7 (Uniprot-TrEMBL)
TIMM22 ProteinQ9Y584 (Uniprot-TrEMBL)
TIMM22ProteinQ9Y584 (Uniprot-TrEMBL)
TIMM23 ComplexComplexREACT_119853 (Reactome)
TIMM23 ProteinO14925 (Uniprot-TrEMBL)
TIMM23 PAM CargoComplexREACT_120146 (Reactome)
TIMM23 PAM Precursor CargoComplexREACT_118867 (Reactome)
TIMM23 SORT CargoComplexREACT_119235 (Reactome)
TIMM23 SORT Precursor CargoComplexREACT_120218 (Reactome)
TIMM44ProteinO43615 (Uniprot-TrEMBL)
TIMM50 ProteinQ3ZCQ8 (Uniprot-TrEMBL)
TIMM8

TIMM13

Protein		ComplexREACT_119483 (Reactome)
TIMM8 TIMM13ComplexREACT_119612 (Reactome)
TIMM9

TIMM10 FXC1 TIM22

Protein		ComplexREACT_119578 (Reactome)
TIMM9

TIMM10

Protein		ComplexREACT_119702 (Reactome)
TIMM9 TIMM10ComplexREACT_118963 (Reactome)
TOMM20 ProteinQ15388 (Uniprot-TrEMBL)
TOMM22 ProteinQ9NS69 (Uniprot-TrEMBL)
TOMM40 ComplexComplexREACT_120217 (Reactome)
TOMM40 ProteinO96008 (Uniprot-TrEMBL)
TOMM5 ProteinQ8N4H5 (Uniprot-TrEMBL)
TOMM6 ProteinQ96B49 (Uniprot-TrEMBL)
TOMM7 ProteinQ9P0U1 (Uniprot-TrEMBL)
TOMM70AProteinO94826 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
4xHC-TIMM10BREACT_118697 (Reactome)
ADPArrowREACT_118696 (Reactome)
ATPREACT_118696 (Reactome)
Cargo of TIMM23 PAMArrowREACT_118696 (Reactome)
Cargo of TIMM23 SORTArrowREACT_118571 (Reactome)
MIA40 ERV1mim-catalysisREACT_118849 (Reactome)
Mitochondrial processing peptidasemim-catalysisREACT_118803 (Reactome)
Mitochondrial processing peptidasemim-catalysisREACT_118813 (Reactome)
PiArrowREACT_118696 (Reactome)
Precursor Cargo of TIMM23 PAMREACT_118832 (Reactome)
Precursor Cargo of TIMM23 SORTREACT_118623 (Reactome)
Proteins Chaperoned by TIMM8 TIMM13REACT_118838 (Reactome)
Proteins Chaperoned by TIMM9 TIMM10REACT_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 Complexmim-catalysisREACT_118792 (Reactome)
TIMM22REACT_118697 (Reactome)
TIMM22mim-catalysisREACT_118820 (Reactome)
TIMM23 ComplexArrowREACT_118571 (Reactome)
TIMM23 ComplexArrowREACT_118696 (Reactome)
TIMM23 ComplexREACT_118623 (Reactome)
TIMM23 ComplexREACT_118832 (Reactome)
TIMM23 PAM CargoREACT_118696 (Reactome)
TIMM23 PAM Cargomim-catalysisREACT_118696 (Reactome)
TIMM23 SORT Cargomim-catalysisREACT_118571 (Reactome)
TIMM8 TIMM13REACT_118838 (Reactome)
TIMM9

TIMM10

Protein		REACT_118697 (Reactome)
TIMM9 TIMM10REACT_118732 (Reactome)
TOMM40 Complexmim-catalysisREACT_118675 (Reactome)
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