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Nature May 2019Mitochondrial biogenesis and functions depend on the import of precursor proteins via the 'translocase of the outer membrane' (TOM complex). Defects in protein import...
Mitochondrial biogenesis and functions depend on the import of precursor proteins via the 'translocase of the outer membrane' (TOM complex). Defects in protein import lead to an accumulation of mitochondrial precursor proteins that induces a range of cellular stress responses. However, constitutive quality-control mechanisms that clear trapped precursor proteins from the TOM channel under non-stress conditions have remained unknown. Here we report that in Saccharomyces cerevisiae Ubx2, which functions in endoplasmic reticulum-associated degradation, is crucial for this quality-control process. A pool of Ubx2 binds to the TOM complex to recruit the AAA ATPase Cdc48 for removal of arrested precursor proteins from the TOM channel. This mitochondrial protein translocation-associated degradation (mitoTAD) pathway continuously monitors the TOM complex under non-stress conditions to prevent clogging of the TOM channel with precursor proteins. The mitoTAD pathway ensures that mitochondria maintain their full protein-import capacity, and protects cells against proteotoxic stress induced by impaired transport of proteins into mitochondria.
Topics: Carrier Proteins; Endoplasmic Reticulum-Associated Degradation; Membrane Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Protein Transport; Proteolysis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Valosin Containing Protein
PubMed: 31118508
DOI: 10.1038/s41586-019-1227-y -
Traffic (Copenhagen, Denmark) Feb 2017Mitochondria have many different functions, the most important one of which is oxidative phosphorylation. They originated from an endosymbiotic event between a bacterium... (Review)
Review
Mitochondria have many different functions, the most important one of which is oxidative phosphorylation. They originated from an endosymbiotic event between a bacterium and an archaeal host cell. It was the evolution of a protein import system that marked the boundary between the endosymbiotic ancestor of the mitochondrion and a true organelle that is under the control of the nucleus. In present day mitochondria more than 95% of all proteins are imported from the cytosol in a proces mediated by hetero-oligomeric protein complexes in the outer and inner mitochondrial membranes. In this review we compare mitochondrial protein import in the best studied model system yeast and the parasitic protozoan Trypanosoma brucei. The 2 organisms are phylogenetically only remotely related. Despite the fact that mitochondrial protein import has the same function in both species, only very few subunits of their import machineries are conserved. Moreover, while yeast has 2 inner membrane protein translocases, one specialized for presequence-containing and one for mitochondrial carrier proteins, T. brucei has a single inner membrane translocase only, that mediates import of both types of substrates. The evolutionary implications of these findings are discussed.
Topics: Cytosol; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Protein Transport; Trypanosoma brucei brucei
PubMed: 27976830
DOI: 10.1111/tra.12463 -
ELife May 2023Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core...
Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog ADP/ATP carrier 2 (Aac2), cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis, and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 causes severe clogging primarily at the translocase of the outer membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.
Topics: Animals; Humans; Mice; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Mitochondria; Mitochondrial ADP, ATP Translocases; Carrier Proteins; Protein Transport; Mitochondrial Proteins; Mitochondrial Membrane Transport Proteins
PubMed: 37129366
DOI: 10.7554/eLife.84330 -
Biological Chemistry Jul 2023Most mitochondrial proteins are nuclear-encoded and imported by the protein import machinery based on specific targeting signals. The proteins that carry an...
Most mitochondrial proteins are nuclear-encoded and imported by the protein import machinery based on specific targeting signals. The proteins that carry an amino-terminal targeting signal (presequence) are imported via the presequence import pathway that involves the translocases of the outer and inner membranes - TOM and TIM23 complexes. In this article, we discuss how mitochondrial matrix and inner membrane precursor proteins are imported along the presequence pathway in with a focus on the dynamics of the TIM23 complex, and further update with some of the key findings that advanced the field in the last few years.
Topics: Protein Transport; Saccharomyces cerevisiae; Mitochondria; Mitochondrial Proteins; Mitochondrial Precursor Protein Import Complex Proteins
PubMed: 37155927
DOI: 10.1515/hsz-2023-0133 -
Journal of Molecular Biology Mar 2015Peroxisomes are unique among the organelles of the endomembrane system. Unlike other organelles that derive most if not all of their proteins from the ER (endoplasmic... (Review)
Review
Peroxisomes are unique among the organelles of the endomembrane system. Unlike other organelles that derive most if not all of their proteins from the ER (endoplasmic reticulum), peroxisomes contain dedicated machineries for import of matrix proteins and insertion of membrane proteins. However, peroxisomes are also able to import a subset of their membrane proteins from the ER. One aspect of peroxisome biology that has remained ill defined is the role the various import pathways play in peroxisome maintenance. In this review, we discuss the available data on matrix and membrane protein import into peroxisomes.
Topics: Animals; Endoplasmic Reticulum; Humans; Membrane Proteins; Molecular Chaperones; Peroxins; Peroxisomes; Protein Folding; Protein Transport; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 25681696
DOI: 10.1016/j.jmb.2015.02.005 -
Trends in Plant Science Jun 2017Cytokinins are phytohormones essential for cytokinesis and many other physiological and developmental processes in planta. Long-distance transport and intercellular... (Review)
Review
Cytokinins are phytohormones essential for cytokinesis and many other physiological and developmental processes in planta. Long-distance transport and intercellular transport have been postulated. For these processes, the existence of cytokinin transporters has been suggested. Recently, a transporter loading the xylem (AtABCG14) and another for cellular import (AtPUP14) have been discovered. AtABCG14 participates in the xylem loading process of cytokinins and contributes to the positive regulation of shoot growth. The cellular importer AtPUP14 is required to suppress cytokinin signaling. A role of a transporter as stop signal is a new paradigm for a hormone transporter.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Cytokinins; Membrane Transport Proteins; Signal Transduction
PubMed: 28372884
DOI: 10.1016/j.tplants.2017.03.003 -
Journal of Experimental Botany Feb 2021Chloroplast-targeted proteins are actively imported into chloroplasts via the machinery spanning the double-layered membranes of chloroplasts. While the key translocons...
Chloroplast-targeted proteins are actively imported into chloroplasts via the machinery spanning the double-layered membranes of chloroplasts. While the key translocons at the outer (TOC) and inner (TIC) membranes of chloroplasts are defined, proteins that interact with the core components to facilitate pre-protein import are continuously being discovered. A DnaJ-like chaperone ORANGE (OR) protein is known to regulate carotenoid biosynthesis as well as plastid biogenesis and development. In this study, we found that OR physically interacts with several Tic proteins including Tic20, Tic40, and Tic110 in the classic TIC core complex of the chloroplast import machinery. Knocking out or and its homolog or-like greatly affects the import efficiency of some photosynthetic and non-photosynthetic pre-proteins. Consistent with the direct interactions of OR with Tic proteins, the binding efficiency assay revealed that the effect of OR occurs at translocation at the inner envelope membrane (i.e. at the TIC complex). OR is able to reduce the Tic40 protein turnover rate through its chaperone activity. Moreover, OR was found to interfere with the interaction between Tic40 and Tic110, and reduces the binding of pre-proteins to Tic110 in aiding their release for translocation and processing. Our findings suggest that OR plays a new and regulatory role in stabilizing key translocons and in facilitating the late stage of plastid pre-protein translocation to regulate plastid pre-protein import.
Topics: Arabidopsis; Arabidopsis Proteins; Chloroplast Proteins; Chloroplasts; HSP40 Heat-Shock Proteins; Membrane Proteins; Molecular Chaperones; Protein Transport
PubMed: 33165598
DOI: 10.1093/jxb/eraa528 -
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 -
Biochemical Society Transactions Feb 2021Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the... (Review)
Review
Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.
Topics: Animals; Disulfides; Humans; Metabolic Networks and Pathways; Mitochondria; Mitochondrial Precursor Protein Import Complex Proteins; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33599699
DOI: 10.1042/BST20190232 -
Biochemistry. Biokhimiia Jun 2018Many mitochondrial genes have been transferred to the nucleus in course of evolution. The products of expression of these genes, being still necessary for organelle... (Review)
Review
Many mitochondrial genes have been transferred to the nucleus in course of evolution. The products of expression of these genes, being still necessary for organelle function, are imported there from the cytosol. Molecular mechanisms of protein import are studied much deeper than those of nucleic acids. The latter, it seems to us, retards the development of mitochondrial genome editing technologies. In this review, we describe mechanisms of DNA, RNA, and protein import into mitochondria of different eukaryotes. The description is given for the natural processes, as well as for artificial targeting of macromolecules into mitochondria for therapy. Also, we discuss different approaches to introduce changes into the mitochondrial DNA sequence.
Topics: Biopolymers; Eukaryota; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Nucleic Acids; RNA, Transfer
PubMed: 30195322
DOI: 10.1134/S0006297918060032