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Annual Review of Biochemistry Jun 2017Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized... (Review)
Review
Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized as precursors in the cytosol and are imported into mitochondria by five transport pathways. The protein import machineries of the mitochondrial membranes and aqueous compartments reveal a remarkable variability of mechanisms for protein recognition, translocation, and sorting. The protein translocases do not operate as separate entities but are connected to each other and to machineries with functions in energetics, membrane organization, and quality control. Here, we discuss the versatility and dynamic organization of the mitochondrial protein import machineries. Elucidating the molecular mechanisms of mitochondrial protein translocation is crucial for understanding the integration of protein translocases into a large network that controls organelle biogenesis, function, and dynamics.
Topics: Carrier Proteins; Eukaryotic Cells; Gene Expression; Humans; Isoenzymes; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Organelle Biogenesis; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Precursors; Protein Transport
PubMed: 28301740
DOI: 10.1146/annurev-biochem-060815-014352 -
Journal of Biochemistry Jun 1998The intracellular sorting of newly synthesized precursor proteins (preproteins) to mitochondria depends on the "mitochondria-targeting sequence" (MTS), which is located... (Review)
Review
The intracellular sorting of newly synthesized precursor proteins (preproteins) to mitochondria depends on the "mitochondria-targeting sequence" (MTS), which is located at the amino termini of the preproteins. MTS is required, however, not only for targeting newly synthesized preproteins to mitochondria, but also for all the following steps along the mitochondrial protein import pathway. MTS of nascent preproteins is first recognized by a cytoplasmic molecular chaperone, MSF, and then by Tom70 and Tom20 of the mitochondrial outer membrane receptor complex, Tom5 and Tom40 of the outer membrane protein translocation machinery, Tim23 of the inner membrane protein translocation machinery, and finally the processing peptidase, MPP, in the matrix. MTS is a multi-role sorting sequence which specifically interacts with various components along the mitochondrial protein import pathway. Recognition of MTS at multiple steps during the import of preproteins may contribute to the strict sorting of proteins destined for mitochondria.
Topics: 14-3-3 Proteins; Amino Acid Sequence; Animals; Biological Transport; Carrier Proteins; Fungal Proteins; Humans; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Molecular Chaperones; Molecular Sequence Data; Proteins; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae Proteins; Sequence Analysis
PubMed: 9603986
DOI: 10.1093/oxfordjournals.jbchem.a022036 -
Nature Mar 2017Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many...
Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins. Here we show that, in yeast, cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates that form under heat shock contain both cytosolic and mitochondrial proteins and interact with the mitochondrial import complex. Many aggregation-prone proteins enter the mitochondrial intermembrane space and matrix after heat shock, and some do so even without stress. Timely dissolution of cytosolic aggregates requires the mitochondrial import machinery and proteases. Blocking mitochondrial import but not proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells.
Topics: Cell Line; Cytosol; HSP70 Heat-Shock Proteins; Heat-Shock Response; Homeostasis; Humans; Mitochondria; Mitochondrial Proteins; Peptide Hydrolases; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Folding; Protein Refolding; Protein Stability; Protein Transport; Proteins; Proteolysis; Saccharomyces cerevisiae
PubMed: 28241148
DOI: 10.1038/nature21695 -
Biochemical Society Transactions Oct 2015The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across... (Review)
Review
The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across the membrane. ABC transporters can be divided into exporters and importers; importers mediate the uptake of essential nutrients into cells and are found predominantly in prokaryotes whereas exporters transport molecules out of cells or into organelles and are found in all organisms. ABC exporters have been linked with multi-drug resistance in both bacterial and eukaryotic cells. ABC transporters are powered by the hydrolysis of ATP and transport their substrate via the alternating access mechanism, whereby the protein alternates between a conformation in which the substrate-binding site is accessible from the outside of the membrane, outward-facing and one in which it is inward-facing. In this mini-review, the structures of different ABC transporter types in different conformations are presented within the context of the alternating access mechanism and how they have shaped our current understanding of the mechanism of ABC transporters.
Topics: ATP-Binding Cassette Transporters; Adenosine Triphosphatases; Animals; Biocatalysis; Biological Transport, Active; Drug Resistance, Multiple; Humans; Isoenzymes; Models, Molecular; Mutation; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary
PubMed: 26517899
DOI: 10.1042/BST20150047 -
The FEBS Journal Nov 2022Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the... (Review)
Review
Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100, and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP-powered Ycf2 complex consisting of several FtsH-like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co-chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin-proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.
Topics: Plant Proteins; Chloroplasts; Chloroplast Proteins; Protein Transport; Molecular Chaperones; Protein Precursors
PubMed: 35472255
DOI: 10.1111/febs.16464 -
FEBS Letters Apr 2021The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction... (Review)
Review
The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co-ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.
Topics: Animals; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Protein Transport
PubMed: 33314127
DOI: 10.1002/1873-3468.14022 -
Biochimica Et Biophysica Acta.... Jan 2021Outer membrane proteins integrate mitochondria into the cellular environment. They warrant exchange of small molecules like metabolites and ions, transport proteins into... (Review)
Review
Outer membrane proteins integrate mitochondria into the cellular environment. They warrant exchange of small molecules like metabolites and ions, transport proteins into mitochondria, form contact sites to other cellular organelles for lipid exchange, constitute a signaling platform for apoptosis and inflammation and mediate organelle fusion and fission. The outer membrane contains two types of integral membrane proteins. Proteins with a transmembrane β-barrel structure and proteins with a single or multiple α-helical membrane spans. All outer membrane proteins are produced on cytosolic ribosomes and imported into the target organelle. Precursors of β-barrel and α-helical proteins are transported into the outer membrane via distinct import routes. The translocase of the outer membrane (TOM complex) transports β-barrel precursors across the outer membrane and the sorting and assembly machinery (SAM complex) inserts them into the target membrane. The mitochondrial import (MIM) complex constitutes the major integration site for α-helical embedded proteins. The import of some MIM-substrates involves TOM receptors, while others are imported in a TOM-independent manner. Remarkably, TOM, SAM and MIM complexes dynamically interact to import a large set of different proteins and to coordinate their assembly into protein complexes. Thus, protein import into the mitochondrial outer membrane involves a dynamic platform of protein translocases.
Topics: Animals; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Protein Transport
PubMed: 33035511
DOI: 10.1016/j.bbabio.2020.148323 -
IUBMB Life 2001Most mitochondrial proteins are encoded by the nuclear genome and thus have to be imported into mitochondria from the cytosol. Protein translocation across and into the... (Review)
Review
Most mitochondrial proteins are encoded by the nuclear genome and thus have to be imported into mitochondria from the cytosol. Protein translocation across and into the mitochondrial membranes is a multistep process facilitated by the coordinated action of at least four specialized translocation systems in the outer and inner membranes of mitochondria. The outer membrane contains one general translocase, the TOM complex, whereas three distinct translocases are located in the inner membrane, which facilitates translocation of different classes of preproteins. The TIM23 complex mediates import of matrix-targeted preproteins with N-terminal presequences, whereas hydrophobic preproteins with internal targeting signals are inserted into the inner membrane via the TIM22 complex. The OXA translocase mediates the insertion of preproteins from the matrix space into the inner membrane. This review focuses on the structural organization and function of the import machinery of the model organisms of Saccharomyces cerevisiae and Neurospora crassa. In addition, the molecular basis of a new human mitochondrial disorder is discussed, the Mohr-Tranebjaerg syndrome. This is the first known disease, which is caused by an impaired mitochondrial protein import machinery leading to progressive neurodegeneration.
Topics: Animals; Carrier Proteins; Humans; Intracellular Membranes; Macromolecular Substances; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Protein Transport; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 11798021
DOI: 10.1080/15216540152845894 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are organelles that play an important role in many cellular tasks. The functionality of peroxisomes depends on the proper import of their matrix proteins.... (Review)
Review
Peroxisomes are organelles that play an important role in many cellular tasks. The functionality of peroxisomes depends on the proper import of their matrix proteins. Peroxisomal matrix proteins are imported posttranslationally in a folded, sometimes even oligomeric state. They harbor a peroxisomal targeting sequence (PTS), which is recognized by dynamic PTS-receptors in the cytosol. The PTS-receptors ferry the cargo to the peroxisomal membrane, where they become part of a transient import pore and then release the cargo into the peroxisomal lumen. Subsequentially, the PTS-receptors are ubiquitinated in order to mark them for the export-machinery, which releases them back to the cytosol. Upon deubiquitination, the PTS-receptors can facilitate further rounds of cargo import. Because the ubiquitination of the receptors is an essential step in the import cycle, it also represents a central regulatory element that governs peroxisomal dynamics. In this review we want to give an introduction to the functional role played by ubiquitination during peroxisomal protein import and highlight the mechanistic concepts that have emerged based on data derived from different species since the discovery of the first ubiquitinated peroxin 15years ago. Moreover, we discuss future tasks and the potential of using advanced technologies for investigating further details of peroxisomal protein transport.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Animals; Eukaryotic Cells; Gene Expression Regulation; Humans; Membrane Proteins; Peroxisomes; Plants; Protein Isoforms; Protein Structure, Tertiary; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 26367801
DOI: 10.1016/j.bbamcr.2015.09.010 -
Biochimica Et Biophysica Acta Feb 2013Chloroplasts are essential organelles in the cells of plants and algae. The functions of these specialized plastids are largely dependent on the ~3000 proteins residing... (Review)
Review
Chloroplasts are essential organelles in the cells of plants and algae. The functions of these specialized plastids are largely dependent on the ~3000 proteins residing in the organelle. Although chloroplasts are capable of a limited amount of semiautonomous protein synthesis - their genomes encode ~100 proteins - they must import more than 95% of their proteins after synthesis in the cytosol. Imported proteins generally possess an N-terminal extension termed a transit peptide. The importing translocons are made up of two complexes in the outer and inner envelope membranes, the so-called Toc and Tic machineries, respectively. The Toc complex contains two precursor receptors, Toc159 and Toc34, a protein channel, Toc75, and a peripheral component, Toc64/OEP64. The Tic complex consists of as many as eight components, namely Tic22, Tic110, Tic40, Tic20, Tic21 Tic62, Tic55 and Tic32. This general Toc/Tic import pathway, worked out largely in pea chloroplasts, appears to operate in chloroplasts in all green plants, albeit with significant modifications. Sub-complexes of the Toc and Tic machineries are proposed to exist to satisfy different substrate-, tissue-, cell- and developmental requirements. In this review, we summarize our understanding of the functions of Toc and Tic components, comparing these components of the import machinery in green algae through trees. We emphasize recent findings that point to growing complexities of chloroplast protein import process, and use the evolutionary relationships between proteins of different species in an attempt to define the essential core translocon components and those more likely to be responsible for regulation. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.
Topics: Amino Acid Sequence; Chloroplast Proteins; Chloroplasts; Molecular Sequence Data; Plant Proteins; Plants; Protein Transport; Trees
PubMed: 23063942
DOI: 10.1016/j.bbamcr.2012.10.002