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Review
. 2015 Mar;24(3):277-97.
doi: 10.1002/pro.2625. Epub 2015 Feb 12.

Role of membrane contact sites in protein import into mitochondria

Susanne E Horvath  1 , Heike Rampelt, Silke Oeljeklaus, Bettina Warscheid, Martin van der Laan, Nikolaus Pfanner
Affiliations
Review

Role of membrane contact sites in protein import into mitochondria

Susanne E Horvath et al. Protein Sci. 2015 Mar.

Abstract

Mitochondria import more than 1,000 different proteins from the cytosol. The proteins are synthesized as precursors on cytosolic ribosomes and are translocated by protein transport machineries of the mitochondrial membranes. Five main pathways for protein import into mitochondria have been identified. Most pathways use the translocase of the outer mitochondrial membrane (TOM) as the entry gate into mitochondria. Depending on specific signals contained in the precursors, the proteins are subsequently transferred to different intramitochondrial translocases. In this article, we discuss the connection between protein import and mitochondrial membrane architecture. Mitochondria possess two membranes. It is a long-standing question how contact sites between outer and inner membranes are formed and which role the contact sites play in the translocation of precursor proteins. A major translocation contact site is formed between the TOM complex and the presequence translocase of the inner membrane (TIM23 complex), promoting transfer of presequence-carrying preproteins to the mitochondrial inner membrane and matrix. Recent findings led to the identification of contact sites that involve the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. MICOS plays a dual role. It is crucial for maintaining the inner membrane cristae architecture and forms contacts sites to the outer membrane that promote translocation of precursor proteins into the intermembrane space and outer membrane of mitochondria. The view is emerging that the mitochondrial protein translocases do not function as independent units, but are embedded in a network of interactions with machineries that control mitochondrial activity and architecture.

Keywords: MICOS; contact site; membrane architecture; mitochondria; protein sorting; protein translocase.

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Figures

Figure 1
Figure 1
Biogenesis of mitochondrial proteins. Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria by the translocase of the outer membrane (TOM). (i) Presequence-carrying preproteins are transferred from TOM to the presequence translocase of the inner membrane (TIM23). Hydrophilic preproteins are transported into the matrix with the help of the presequence translocase-associated motor (PAM). Preproteins with hydrophobic sorting signal are arrested in the TIM23 complex and are laterally released into the inner membrane (IM). The presequences are proteolytically removed by the mitochondrial processing peptidase (MPP). (ii) The precursors of multispanning inner membrane proteins like the carrier proteins are imported via TOM, the small TIM chaperones of the intermembrane space (IMS) and the carrier translocase of the inner membrane (TIM22). (iii) IMS proteins with cysteine motifs are imported via TOM and the mitochondrial IMS import and assembly (MIA) machinery. (iv) The precursors of outer membrane (OM) β-barrel proteins use TOM, small TIM chaperones and the sorting and assembly machinery (SAM) for insertion into the outer membrane. (v) For α-helical outer membrane proteins, different pathways have been described. Shown is the import of a precursor protein via the mitochondrial import (MIM) complex. (vi) A small number of hydrophobic proteins are encoded by mtDNA and synthesized in the matrix. These proteins are typically exported into the inner membrane by the cytochrome oxidase activity (OXA) translocase. Δψ, membrane potential across the inner mitochondrial membrane (drives protein import via TIM23 and TIM22).
Figure 2
Figure 2
Translocation contact sites as core of the presequence pathway of mitochondria. (A) Matrix-targeted precursor proteins typically carry cleavable amino-terminal presequences. The presequences are recognized by receptors of the translocase of the outer membrane (TOM). Upon translocation through the Tom40 channel, the preproteins are transferred to the presequence translocase of the inner membrane (TIM23 complex). Several Tom and Tim proteins cooperate in the formation of dynamic TOM-TIM23 translocation contact sites. Two forms of the TIM23 complex are in dynamic exchange with each other. Both TIM23 forms are involved in the formation of TOM-TIM23 supercomplexes. In an early stage of translocation, Tim21 is associated with TIM23, whereas in later stages, the presequence translocase-associated motor (PAM) is associated with TIM23. The mitochondrial processing peptidase (MPP) removes the presequences. OM, outer membrane; IMS, intermembrane space; IM, inner membrane. (B) Cleavable preproteins inserted into the inner membrane (IM) carry a hydrophobic sorting signal behind the positively charged matrix targeting signal. Insertion of these preproteins into the inner membrane can be mediated by the Tim21-containing TIM23 complex without PAM. Mgr2 functions as lateral gatekeeper of the TIM23 complex and controls the proper sorting of preproteins into the inner membrane. The respiratory chain complexes III and IV interact with the Tim21-containing TIM23 complex and stimulate the Δψ-dependent preprotein insertion. (C) The outer membrane protein Om45 uses an unusual biogenesis pathway that involves TOM, TIM23 and the mitochondrial import (MIM) complex.
Figure 3
Figure 3
Mitochondrial contact site and cristae organizing system and protein import into intermembrane space. (A) The mitochondrial inner membrane consists of the inner boundary membrane (IBM), cristae membranes and the connecting crista junctions. Protein translocases are enriched in the IBM, whereas respiratory complexes and the F1Fo-ATP synthase are enriched in cristae membranes. The MICOS complex is enriched at crista junctions and exposes protein domains into the intermembrane space (IMS). MICOS is crucial for maintenance of the cristae structure and forms multiple contact sites with outer membrane (OM) protein complexes. Fzo1, Ugo1, and Mgm1, components of the mitochondrial membrane fusion machinery. (B) The precursors of intermembrane space proteins with cysteine motifs are translocated through the Tom40 channel and are recognized by the oxidoreductase Mia40 that functions as receptor in the intermembrane space. Mic60 interacts with TOM and Mia40 and thus positions Mia40 close to the Tom40 channel. In cooperation with the sulfhydryl oxidase Erv1, Mia40 oxidizes the imported proteins, leading to disulfide formation and folding of the proteins.
Figure 4
Figure 4
Biogenesis of mitochondrial outer membrane proteins and ER-mitochondria contact sites. Left half, β-barrel proteins of the outer membrane (OM) are imported into mitochondria via TOM, the small TIM chaperones of the intermembrane space (IMS) and the sorting and assembly machinery (SAM). MICOS interacts with TOM and SAM and stimulates β-barrel biogenesis. The transient interaction of Mic60 with TOM promotes translocation of β-barrel precursors to the intermembrane space. Right half, the SAM complex is in dynamic exchange with the ER-mitochondria encounter structure (ERMES) via the protein Mdm10. Tom7 binds to the SAM-free form of Mdm10 that can associate with ERMES. ERMES is composed of Mdm10, Mdm34, the adaptor protein Mdm12, the regulatory protein Gem1 and the ER localized protein Mmm1. MICOS and ERMES form genetic interactions.
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