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J Biol Chem, Vol. 274, Issue 50, 35285-35288, December 10, 1999
and
From the School of Biological Sciences, University of
Manchester, Oxford Road, Manchester M13 9PT, United Kingdom and
§ Biozentrum, University of Basel,
CH-4056 Basel, Switzerland
The mitochondrial inner membrane of
most organisms studied so far contains about a dozen proteins made by
the mitochondrial genetic system and on the order of 102
proteins imported from the cytoplasm. This review briefly describes the
two major pathways by which proteins made inside or outside the
mitochondria are inserted into the inner membrane. These pathways were
discovered only during the past few years; one of them involves a novel
family of chaperone-like proteins in the mitochondrial intermembrane space.
Import of proteins from the cytoplasm into mitochondria occurs by
distinct routes that are dictated by the properties and final
destination of each protein within the mitochondria (1-3). However,
most of the different routes described until recently have been
variants of the general "matrix pathway." In this pathway, a
protein carrying a positively charged amphiphilic helix at its N
terminus is bound by cytosolic chaperones, delivered to an array of
import receptors on the mitochondrial surface, and then transported across two distinct, hetero-oligomeric protein translocation channels, the TOM complex in the outer membrane and the TIM23 complex in the
inner membrane. During transport, the two complexes are transiently linked by the translocating precursor chain (4, 5). Transport across
the TOM complex appears to be driven by binding of the basic N-terminal
"presequence" to a series of acidic receptor domains of increasing
avidity ("acid chain hypothesis") (6, 7); insertion of the
presequence into the TIM23 complex is driven electrophoretically by the
potential across the inner membrane; and complete transport of the
precursor into the matrix is driven by an ATP-powered import motor
attached to the inner mouth of the TIM23 complex. Proteins destined for
compartments other than the matrix can diverge from the general matrix
pathway at different points (8-10). Some proteins destined for the
outer membrane can arrest in the TOM complex and then escape into the
outer membrane (11); and some intermembrane space proteins can arrest
in the TIM23 complex and then be proteolytically released into the
intermembrane space (8).
A few years ago it seemed likely that a variation of this general
matrix pathway would also sort proteins to the inner membrane. According to this view, a protein destined for the inner membrane would
arrest in the TIM23 complex and escape "sidewise" into the phospholipid bilayer of the inner membrane. So far, however, no inner
membrane protein has been shown to follow such a pathway. Arrest in the
TIM23 complex has only been found for some proteins destined for the
intermembrane space.
The TIM23 complex functioning in the matrix pathway consists of
the two integral membrane proteins Tim17p and Tim23p, which together
form a gated, protein-conducting channel across the mitochondrial inner
membrane. Most precursors enter this channel with their N-terminal
matrix signal first, presumably in an unfolded conformation. A few
precursors appear to contain an internal matrix signal and may insert
into the channel as a loop (12). As the channel diameter of the TIM23
complex is at most 20 Å (13), it is not clear how this channel can
accommodate a looped polypeptide chain.
Proteins targeted to the aqueous intermembrane space by arrest in the
TIM23 complex carry a matrix signal followed by an uncharged "sorting
signal" (14). We have proposed that the matrix signal directs the
precursor into the TIM23 complex, that the sorting signal causes it to
become stuck there, and that the mature protein is released from the
stuck translocation intermediate into the intermembrane space by
proteolytic cleavage on the outer face of the inner membrane ("stop
transfer" model; Refs. 8 and 14). The alternative "conservative
sorting" model proposed that the entire bipartite signal enters the
matrix and then loops back into the inner membrane to direct re-export
of the entire precursor chain into the intermembrane space (15, 16).
Both models invoked the same proteolytic cleavage of the stuck
translocation intermediate but predicted a different membrane
environment of the intermediate's sorting signal. The stop transfer
model predicted a similar environment as for a precursor en
route to the matrix, whereas the conservative sorting predicted a
location in a distinct re-export system. To test these predictions, we
generated the translocation intermediate of an intermembrane
space-targeted precursor that had already reached the intermembrane
space but had not yet been proteolytically released from its anchor
site in the inner membrane. Next to its sorting signal, the
intermediate carried a unique cysteine that could be cross-linked with
up to 80% efficiency to an 11-kDa inner membrane protein, which we
termed Tim11p (17). The unusually high cross-linking efficiency argued
against the possibility that the sorting signal of the translocation
intermediate looped through the matrix. Tim11p was also efficiently
cross-linked to the translocation intermediate of a matrix-targeted
precursor whose complete import into the matrix was arrested by
depleting the matrix of ATP. As reported by us (17), Tim11 is neither a
sorting signal receptor nor part of the TIM23 complex. Subsequent work
(18, 19)1 identified it as a
protein associated with the F1F0-ATPase
complex. Proximity of the ATPase complex to a protein import channel
has also been observed in chloroplasts (20). Although a role of Tim11p
in protein sorting is still uncertain, the protein has served as a
unique topological marker to show that the molecular environment of the
sorting signal during the final step of protein sorting to the
intermembrane space is very similar or identical to that of a precursor
en route to the matrix (Fig.
1).
Models explaining protein import into the inner membrane through
docked TOM and TIM23 complexes followed by arrest of the precursor in
the inner membrane have always faced a major problem; docking of the
two protein transport channels is thought to be effected by interaction
of a precursor's N-terminal basic matrix signal with an acidic Tim23
domain on the outer face of the inner membrane, but many polytopic
inner membrane proteins lack a basic targeting signal at their N
terminus. Instead, they contain one or several internal signals that
remain poorly characterized (21, 22). Among the most abundant of such
proteins are the metabolite transporters, a protein family that has 34 members in Saccharomyces cerevisiae and includes the ADP/ATP
transporter (AAC). How can these insoluble proteins cross the aqueous
intermembrane space if there is no mechanism that induces docking
between the TOM and the TIM23 complexes? These precursors could
negotiate the aqueous divide between the two membranes with the help of
soluble chaperones, but efforts to detect chaperones in the
intermembrane space had been unsuccessful.
Recent work has now uncovered chaperone-like proteins in the
intermembrane space that are part of a novel machinery dedicated to
importing inner membrane proteins. An important advance was the
discovery that Tim22p, an inner membrane protein of yeast homologous to
Tim23p, mediates import of carrier proteins into the inner membrane but
not general protein import into the matrix (23). Genetic studies
identified two partner subunits of Tim22p: a membrane-embedded 54-kDa
protein termed Tim54p (24) and a peripheral 12-kDa protein termed
Tim12p (25, 26). Tim12 had been discovered before (and named Mrs5p) as
an extragenic suppressor of mutations blocking splicing of
mitochondrial RNA (27). The suppressor screen had also netted the
protein Mrs11p (28), a 10-kDa homolog of Tim12p later renamed Tim10p.
Tim10p was located in the soluble intermembrane space whereas Tim12p
was bound to the outer surface of the inner membrane. Each of these two
proteins was essential for viability. As most of the known essential
mitochondrial proteins participate in protein import (1-3, 29), these
newly discovered proteins appeared to be parts of a novel protein
import system (Fig. 2).
Tim10p exists in large molar excess over Tim12p. Most of it is found in
a 70-kDa complex in the intermembrane space, and the remainder is
located in a 300-kDa membrane-embedded complex (the so-called TIM22
complex) that contains all of Tim12p, Tim22p, and Tim54p. A partner
protein of Tim10p in the 70-kDa complex was found by searching for
extragenic suppressors of a temperature-sensitive mutation in Tim10p.
This screen netted a mutant allele of a 9-kDa protein (termed Tim9p)
with the following properties. Its sequence was 25% identical to
Tim10p; it was essential for viability; and most of it was associated
with Tim10p in the 70-kDa intermembrane space complex. The properties
of the chromatographically purified complex (30) and isotopic in
vivo labeling studies (31) suggest that the most likely
composition of the complex is
(Tim9)3(Tim10)3.
A search of the yeast genome revealed two additional members of the
Tim9p-Tim10p-Tim12p protein family: an 8-kDa protein termed Tim8p and a
13-kDa protein termed Tim13p (32, 33). Tim8p and Tim13p are present in
the soluble intermembrane space as a separate 70-kDa complex that is
distinct from the (Tim9)3(Tim10)3 complex. The
Tim8p-Tim13p complex may also contain Tim9p, but Tim9 is only weakly
bound and completely removed upon chromatographic purification of the
complex. Neither Tim8p nor Tim13p is essential for viability. However,
they appear to interact in vivo with Tim10p as deletion of
either Tim8p or Tim13 is synthetically lethal with a
temperature-sensitive mutation in Tim10p.
How do these proteins coordinate the insertion of the hydrophobic
carriers? Inactivation or deletion of Tim10 blocks import of AAC and
other multispanning inner membrane proteins across the TOM channel,
suggesting that the 70-kDa (Tim9p)3(Tim10p)3 complex binds the incoming precursor and thereby pulls it into the
intermembrane space. In contrast, inactivation or depletion of Tim12
allows import across the TOM channel and binding of the precursor to
the inner membrane but prevents its correct
potential-dependent insertion into the membrane.
Inactivation of Tim12 thus has a similar effect as collapsing of the
potential across the mitochondrial inner membrane. Cross-linking
experiments have verified that Tim10 and Tim12 interact directly with
the incoming precursor proteins. Inactivation or depletion of either
Tim10 or Tim12 has little, if any, effect on the import of proteins
into the matrix or of precursors with bipartite targeting signals into
the intermembrane space (25, 26, 30, 34).
The soluble Tim9p-Tim10p complex is at least 20-fold more abundant than
the membrane-associated TIM22 complex (31).1 Why? One
explanation would be that the two complexes have different affinities
for precursors; the soluble Tim9p-Tim10p complex may be a low affinity
chaperone-like system designed to capture the appropriate precursors as
these emerge from the TOM complex. In contrast, the TIM22 complex may
have a high affinity for a precursor bound to a
(Tim9p)3(Tim10p)3 complex. However, it is still
unclear how Tim9p, Tim10p, and Tim12p interact with the precursor. Do they recognize a specific sequence motif and, if so, which one? It has
been suggested that Tim10p and Tim12p recognize a conserved region
after the first transmembrane domain of mitochondrial metabolite carriers (26, 34). These carriers all have three similar repeats of
approximately 100 amino acids each, which would argue for three distinct internal targeting signals. These signals might be recognized by three complementary motifs in the heterotrimeric Tim9p-Tim10p complex, thereby allowing each complex to bind one precursor molecule. Alternatively, the Tim9p-Tim10p complex might bind hydrophobic sequences with little, if any, sequence preference. This latter model
could explain the observation that the
(Tim9)3(Tim10)3 and Tim8p-Tim13p complexes also
mediate the import of polytopic inner membrane proteins that are
unrelated to the metabolite carrier family (35).
The third insertion pathway for inner membrane proteins involves
yet another large membrane-bound complex, the OXA1 complex. This
complex is named after Oxa1p, its only subunit that has so far been
identified. Oxa1p is a polytopic inner membrane protein with five
potential transmembrane regions. It is made in the cytoplasm with a
transient N-terminal matrix targeting signal, imported into the matrix
by the general matrix import pathway, cleaved to the mature protein,
and then inserted from the matrix into the inner membrane. This
insertion step requires a potential across the inner membrane (36) and
resembles the Sec-independent, How does insertion mediated by the OXA1 complex compare with that
mediated by the TIM22 complex? Both processes require a membrane
potential and insert proteins according to the "positive inside"
rule (40). However, whereas insertion by the TIM22 complex obviously
occurs post-translationally, the mode of insertion mediated by the OXA1
complex is not yet clear. The matrix-located proteins mhsp70 (Ssc1p)
and hsp60 have been reported to function as chaperones for
mitochondrially encoded proteins (41, 42), but it remains to be shown
that these chaperones deliver their cargo to the OXA1 complex.
Insertion of some very hydrophobic mitochondrially made proteins by the
OXA1 pathway may well occur co-translationally. As some features of
this pathway are also found in bacteria (see above), it may reflect the
evolutionary origin of mitochondria from bacterial ancestors. On the
other hand, bacteria appear to lack recognizable homologs of the small
Tim proteins of the mitochondrial intermembrane space. The TIM22
pathway may thus have originated late in the evolution of eukaryotic
cells (Fig. 2).
It was recently reported that DDP1, a small human protein whose
loss causes a severe deafness-dystonia syndrome, is homologous to Tim8p
of yeast (32). As DDP1 was shown to be localized in mitochondria of
mammalian cells and as isolated yeast mitochondria imported
radiolabeled DDP1 into their intermembrane space, the human
deafness-dystonia syndrome is a mitochondrial disease caused by a
defective import system for inner membrane proteins. As the human
genome contains several DDP1 homologs (32), a study of these proteins
should identify additional human diseases of similar etiology.
The Problem
TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
Arrest in the TIM23 Complex
TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
View larger version (28K):
[in a new window]
Fig. 1.
Arrest in the TIM23 complex for protein
sorting to the intermembrane space. Disulfide cross-linking (in
red) shows that the translocation intermediate arrested by
its stop transfer signal (black bar) is in the
same or a very similar molecular environment as a matrix-targeted
precursor arrested by lack of ATP in the matrix. IM, inner
membrane; IMS, intermembrane space; DHFR,
dihydrofolate reductase fused to either an intermembrane space
targeting signal (left) or to a matrix targeting signal
(right).
A Separate "Insertion Complex" in the Inner Membrane
TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
Insertion of Polytopic Proteins from the Matrix
TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
pH-dependent insertion of
polytopic proteins into the bacterial plasma membrane. No component of
that bacterial pathway has as yet been identified. Oxa1p is required
for its own insertion and also mediates the insertion of
mitochondrially synthesized polytopic proteins into the inner membrane
(37-39). Oxa1p may thus be the central component of a protein
insertion machinery that inserts hydrophobic transmembrane regions from
the matrix into the inner membrane.
View larger version (31K):
[in a new window]
Fig. 2.
Different modes of insertion of proteins into
the inner membrane. A, insertion by the TIM22 pathway
involving the 70-kDa (Tim9)3(Tim10)3 and
Tim8p-Tim13p complexes in the aqueous intermembrane space and the
300-kDa TIM22 complex in the inner membrane. The electrochemical
potential 
facilitates insertion. B, insertion from
the matrix involving the OXA1 complex. Both imported and
mitochondrially synthesized proteins can be inserted via this pathway.
The presequence of matrix-targeted precursors that directs
translocation via docking of the TOM to the TIM23 complex is shown as a
positively charged helix. OM, outer membrane; IM,
inner membrane; IMS, intermembrane space; R,
receptor complex in the outer membrane; Rib, mitochondrial
ribosomes.
A Human Disease Linked to Defective Protein Import into the
Mitochondrial Inner Membrane
TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
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FOOTNOTES |
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* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999. Work on this topic was supported by The Royal Society, The Wellcome Trust (to K. T.), the Swiss National Science Foundation, the European Economic Community, the Human Frontiers Science Program, and the Louis-Jeantet Foundation (to G. S.).
¶ To whom correspondence should be addressed. Tel.: 41 61 267 2150; Fax: 41 61 267 2148; E-mail: schatz@ubaclu.unibas.ch.
1 C. Brunner, K. Tokatlidis, and G. Schatz, unpublished data.
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TOP
The Problem
Arrest in the TIM23...
A Separate "Insertion Complex"...
Insertion of Polytopic Proteins...
A Human Disease Linked...
REFERENCES
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L. Lefebvre-Legendre, J. Vaillier, H. Benabdelhak, J. Velours, P. P. Slonimski, and J.-P. di Rago Identification of a Nuclear Gene (FMC1) Required for the Assembly/Stability of Yeast Mitochondrial F1-ATPase in Heat Stress Conditions J. Biol. Chem., February 23, 2001; 276(9): 6789 - 6796. [Abstract] [Full Text] [PDF]
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M. Ii and K. Mihara Insertion of Mitochondrial DNA-encoded F1F0-ATPase Subunit 8 across the Mitochondrial Inner Membrane in Vitro J. Biol. Chem., June 29, 2001; 276(27): 24704 - 24712. [Abstract] [Full Text] [PDF]
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