Mitochondrial protein import (Homo sapiens)
From WikiPathways
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.
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.
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
processing
peptidasetargeting peptides (from inner
membrane proteins)targeting peptides (from matrix
proteins)SORT:Precursor
CargoAnnotated Interactions
processing
peptidaseprocessing
peptidasetargeting peptides (from inner
membrane proteins)targeting peptides (from matrix
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.
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.
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
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.
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.
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.
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.
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.
SORT:Precursor
CargoSORT:Precursor
Cargo