ALR, the multifunctional protein

2015 ◽  
Vol 156 (13) ◽  
pp. 503-509 ◽  
Author(s):  
Tibor Balogh ◽  
András Szarka
Keyword(s):  
Protein Import ◽  
Short Form ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Proper Function ◽  
Laboratory Diagnostics ◽  
Intermembrane Space ◽  
Relay System ◽  
Multifunctional Protein ◽  
Mitochondrial Intermembrane Space

ALR is a mystic protein. It has a so called “long” 22 kDa and a “short” 15 kDa forms. It has been described after partial hepatectomy and it has just been considered as a key protein of liver regeneration. At the beginning of the 21st century it has been revealed that the “long” form is localized in the mitochondrial intermembrane space and it is an element of the mitochondrial protein import and disulphide relay system. Several proteins of the substrates of the mitochondrial disulphide relay system are necessary for the proper function of the mitochondria, thus any mutation of the ALR gene leads to mitochondrial diseases. The “short” form of ALR functions as a secreted extracellular growth factor and it promotes the protection, regeneration and proliferation of hepatocytes. The results gained on the recently generated conditional ALR mutant mice suggest that ALR can play an important role in the pathogenesis of alcoholic and non-alcoholic steatosis. Since the serum level of ALR is modified in several liver diseases it can be a promising marker molecule in laboratory diagnostics. Orv. Hetil., 2015, 156(13), 503–509.

scholarly journals In Vivo Structure-Function Analysis and Redox Interactomes of Leishmania tarentolae Erv

2021 ◽  
Author(s):  
Gino L. Turra ◽  
Linda Liedgens ◽  
Frederik Sommer ◽  
Luzia Schneider ◽  
David Zimmer ◽  
...  
Keyword(s):  
Protein Import ◽  
Function Analysis ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Redox Biology ◽  
Oxidative Protein Folding ◽  
Mitochondrial Intermembrane Space ◽  
New Research

The discovery of the redox proteins Mia40/CHCHD4 and Erv1/ALR, as well as the elucidation of their relevance for oxidative protein folding in the mitochondrial intermembrane space of yeast and mammals, founded a new research topic in redox biology and mitochondrial protein import. The lack of Mia40/CHCHD4 in protist lineages raises fundamental and controversial questions regarding the conservation and evolution of this essential pathway.

scholarly journals Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells

2013 ◽  
Vol 24 (14) ◽  
pp. 2160-2170 ◽  
Author(s):  
Manuel Fischer ◽  
Sebastian Horn ◽  
Anouar Belkacemi ◽  
Kerstin Kojer ◽  
Carmelina Petrungaro ◽  
...  
Keyword(s):  
Protein Oxidation ◽  
Mammalian Cells ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Basic Principles ◽  
Oxidative Folding ◽  
Physiological Conditions ◽  
Mitochondrial Intermembrane Space ◽  
Kinetics Of

Oxidation of cysteine residues to disulfides drives import of many proteins into the intermembrane space of mitochondria. Recent studies in yeast unraveled the basic principles of mitochondrial protein oxidation, but the kinetics under physiological conditions is unknown. We developed assays to follow protein oxidation in living mammalian cells, which reveal that import and oxidative folding of proteins are kinetically and functionally coupled and depend on the oxidoreductase Mia40, the sulfhydryl oxidase augmenter of liver regeneration (ALR), and the intracellular glutathione pool. Kinetics of substrate oxidation depends on the amount of Mia40 and requires tightly balanced amounts of ALR. Mia40-dependent import of Cox19 in human cells depends on the inner membrane potential. Our observations reveal considerable differences in the velocities of mitochondrial import pathways: whereas preproteins with bipartite targeting sequences are imported within seconds, substrates of Mia40 remain in the cytosol for several minutes and apparently escape premature degradation and oxidation.

scholarly journals Mitochondrial protein import: Mia40 facilitates Tim22 translocation into the inner membrane of mitochondria

2013 ◽  
Vol 24 (5) ◽  
pp. 543-554 ◽  
Author(s):  
Lidia Wrobel ◽  
Agata Trojanowska ◽  
Malgorzata E. Sztolsztener ◽  
Agnieszka Chacinska
Keyword(s):  
Disulfide Bonds ◽  
Protein Import ◽  
Noncovalent Interactions ◽  
Mitochondrial Protein ◽  
Central Component ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
Oxidative Folding ◽  
Mitochondrial Intermembrane Space

The mitochondrial intermembrane space assembly (MIA) pathway is generally considered to be dedicated to the redox-dependent import and biogenesis of proteins localized to the intermembrane space of mitochondria. The oxidoreductase Mia40 is a central component of the pathway responsible for the transfer of disulfide bonds to intermembrane space precursor proteins, causing their oxidative folding. Here we present the first evidence that the function of Mia40 is not restricted to the transport and oxidative folding of intermembrane space proteins. We identify Tim22, a multispanning membrane protein and core component of the TIM22 translocase of inner membrane, as a protein with cysteine residues undergoing oxidation during Tim22 biogenesis. We show that Mia40 is involved in the biogenesis and complex assembly of Tim22. Tim22 forms a disulfide-bonded intermediate with Mia40 upon import into mitochondria. Of interest, Mia40 binds the Tim22 precursor also via noncovalent interactions. We propose that Mia40 not only is responsible for disulfide bond formation, but also assists the Tim22 protein in its integration into the inner membrane of mitochondria.

scholarly journals Mitochondrial protein import: precursor oxidation in a ternary complex with disulfide carrier and sulfhydryl oxidase

2008 ◽  
Vol 183 (2) ◽  
pp. 195-202 ◽  
Author(s):  
Diana Stojanovski ◽  
Dusanka Milenkovic ◽  
Judith M. Müller ◽  
Kipros Gabriel ◽  
Agnes Schulze-Specking ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Ternary Complex ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Intermediate Step ◽  
Intermembrane Space ◽  
Sulfhydryl Oxidase ◽  
Mitochondrial Protein Import ◽  
Substrate Protein ◽  
Mitochondrial Intermembrane Space

The biogenesis of mitochondrial intermembrane space proteins depends on specific machinery that transfers disulfide bonds to precursor proteins. The machinery shares features with protein relays for disulfide bond formation in the bacterial periplasm and endoplasmic reticulum. A disulfide-generating enzyme/sulfhydryl oxidase oxidizes a disulfide carrier protein, which in turn transfers a disulfide to the substrate protein. Current views suggest that the disulfide carrier alternates between binding to the oxidase and the substrate. We have analyzed the cooperation of the disulfide relay components during import of precursors into mitochondria and identified a ternary complex of all three components. The ternary complex represents a transient and intermediate step in the oxidation of intermembrane space precursors, where the oxidase Erv1 promotes disulfide transfer to the precursor while both oxidase and precursor are associated with the disulfide carrier Mia40.

Dynamic organization of the mitochondrial protein import machinery

2016 ◽  
Vol 397 (11) ◽  
pp. 1097-1114 ◽  
Author(s):  
Sebastian P. Straub ◽  
Sebastian B. Stiller ◽  
Nils Wiedemann ◽  
Nikolaus Pfanner
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Membrane Dynamics ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Dynamic Cooperation

Abstract Mitochondria contain elaborate machineries for the import of precursor proteins from the cytosol. The translocase of the outer mitochondrial membrane (TOM) performs the initial import of precursor proteins and transfers the precursors to downstream translocases, including the presequence translocase and the carrier translocase of the inner membrane, the mitochondrial import and assembly machinery of the intermembrane space, and the sorting and assembly machinery of the outer membrane. Although the protein translocases can function as separate entities in vitro, recent studies revealed a close and dynamic cooperation of the protein import machineries to facilitate efficient transfer of precursor proteins in vivo. In addition, protein translocases were found to transiently interact with distinct machineries that function in the respiratory chain or in the maintenance of mitochondrial membrane architecture. Mitochondrial protein import is embedded in a regulatory network that ensures protein biogenesis, membrane dynamics, bioenergetic activity and quality control.

scholarly journals Evolution of mitochondrial protein import – lessons from trypanosomes

2020 ◽  
Vol 401 (6-7) ◽  
pp. 663-676 ◽  
Author(s):  
André Schneider
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Protein Import ◽  
Outer Membrane Proteins ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
System A ◽  
Import Receptors ◽  
Inner Membrane Protein

AbstractThe evolution of mitochondrial protein import and the systems that mediate it marks the boundary between the endosymbiotic ancestor of mitochondria and a true organelle that is under the control of the nucleus. Protein import has been studied in great detail in Saccharomyces cerevisiae. More recently, it has also been extensively investigated in the parasitic protozoan Trypanosoma brucei, making it arguably the second best studied system. A comparative analysis of the protein import complexes of yeast and trypanosomes is provided. Together with data from other systems, this allows to reconstruct the ancestral features of import complexes that were present in the last eukaryotic common ancestor (LECA) and to identify which subunits were added later in evolution. How these data can be translated into plausible scenarios is discussed, providing insights into the evolution of (i) outer membrane protein import receptors, (ii) proteins involved in biogenesis of α-helically anchored outer membrane proteins, and (iii) of the intermembrane space import and assembly system. Finally, it is shown that the unusual presequence-associated import motor of trypanosomes suggests a scenario of how the two ancestral inner membrane protein translocases present in LECA evolved into the single bifunctional one found in extant trypanosomes.

scholarly journals Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23

2019 ◽  
Vol 116 (33) ◽  
pp. 16593-16602 ◽  
Author(s):  
Svitlana Yablonska ◽  
Vinitha Ganesan ◽  
Lisa M. Ferrando ◽  
JinHo Kim ◽  
Anna Pyzel ◽  
...  
Keyword(s):  
Cell Lines ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Biological Significance ◽  
Intermembrane Space ◽  
Mutant Huntingtin ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
Mitochondrial Proteome ◽  
Brain Tissues

Mutant huntingtin (mHTT), the causative protein in Huntington’s disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.

scholarly journals Mia40 is a trans-site receptor that drives protein import into the mitochondrial intermembrane space by hydrophobic substrate binding

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Valentina Peleh ◽  
Emmanuelle Cordat ◽  
Johannes M Herrmann
Keyword(s):  
Disulfide Bonds ◽  
Protein Import ◽  
Protein Translocation ◽  
Hydrophobic Interactions ◽  
Substrate Binding ◽  
Intermembrane Space ◽  
Cysteine Motif ◽  
Mitochondrial Intermembrane Space ◽  
Necessary And Sufficient ◽  
Yeast Mutants

Many proteins of the mitochondrial IMS contain conserved cysteines that are oxidized to disulfide bonds during their import. The conserved IMS protein Mia40 is essential for the oxidation and import of these proteins. Mia40 consists of two functional elements: an N-terminal cysteine-proline-cysteine motif conferring substrate oxidation, and a C-terminal hydrophobic pocket for substrate binding. In this study, we generated yeast mutants to dissect both Mia40 activities genetically and biochemically. Thereby we show that the substrate-binding domain of Mia40 is both necessary and sufficient to promote protein import, indicating that trapping by Mia40 drives protein translocation. An oxidase-deficient Mia40 mutant is inviable, but can be partially rescued by the addition of the chemical oxidant diamide. Our results indicate that Mia40 predominantly serves as a trans-site receptor of mitochondria that binds incoming proteins via hydrophobic interactions thereby mediating protein translocation across the outer membrane by a ‘holding trap’ rather than a ‘folding trap’ mechanism.

scholarly journals The biogenesis of mitochondrial intermembrane space proteins

2020 ◽  
Vol 401 (6-7) ◽  
pp. 737-747 ◽  
Author(s):  
Ruairidh Edwards ◽  
Sarah Gerlich ◽  
Kostas Tokatlidis
Keyword(s):  
Protein Import ◽  
Cellular Stress ◽  
Stress Conditions ◽  
Intermembrane Space ◽  
Dynamic Changes ◽  
Inner Membrane ◽  
Integrated Network ◽  
Response To Stress ◽  
Mitochondrial Intermembrane Space

AbstractThe mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understanding the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness.

scholarly journals Ups1p and Ups2p antagonistically regulate cardiolipin metabolism in mitochondria

2009 ◽  
Vol 185 (6) ◽  
pp. 1029-1045 ◽  
Author(s):  
Yasushi Tamura ◽  
Toshiya Endo ◽  
Miho Iijima ◽  
Hiromi Sesaki
Keyword(s):  
Fatty Acid ◽  
Molecular Mechanism ◽  
Protein Import ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Growth Defects ◽  
Mitochondrial Inner Membrane ◽  
Synthetic Growth

Cardiolipin, a unique phospholipid composed of four fatty acid chains, is located mainly in the mitochondrial inner membrane (IM). Cardiolipin is required for the integrity of several protein complexes in the IM, including the TIM23 translocase, a dynamic complex which mediates protein import into the mitochondria through interactions with the import motor presequence translocase–associated motor (PAM). In this study, we report that two homologous intermembrane space proteins, Ups1p and Ups2p, control cardiolipin metabolism and affect the assembly state of TIM23 and its association with PAM in an opposing manner. In ups1Δ mitochondria, cardiolipin levels were decreased, and the TIM23 translocase showed altered conformation and decreased association with PAM, leading to defects in mitochondrial protein import. Strikingly, loss of Ups2p restored normal cardiolipin levels and rescued TIM23 defects in ups1Δ mitochondria. Furthermore, we observed synthetic growth defects in ups mutants in combination with loss of Pam17p, which controls the integrity of PAM. Our findings provide a novel molecular mechanism for the regulation of cardiolipin metabolism.

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