scholarly journals Coupling of import and assembly pathways in mitochondrial protein biogenesis

2019 ◽  
Vol 401 (1) ◽  
pp. 117-129 ◽  
Author(s):  
Alexander Grevel ◽  
Nikolaus Pfanner ◽  
Thomas Becker
Keyword(s):  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Outer Mitochondrial Membrane ◽  
Protein Biogenesis ◽  
Precursor Proteins ◽  
Oligomeric Assembly ◽  
And Function ◽  
Assembly Pathways ◽  
Partner Proteins

Abstract Biogenesis and function of mitochondria depend on the import of about 1000 precursor proteins that are produced on cytosolic ribosomes. The translocase of the outer membrane (TOM) forms the entry gate for most proteins. After passage through the TOM channel, dedicated preprotein translocases sort the precursor proteins into the mitochondrial subcompartments. Many proteins have to be assembled into oligomeric membrane-integrated complexes in order to perform their functions. In this review, we discuss a dual role of mitochondrial preprotein translocases in protein translocation and oligomeric assembly, focusing on the biogenesis of the TOM complex and the respiratory chain. The sorting and assembly machinery (SAM) of the outer mitochondrial membrane forms a dynamic platform for coupling transport and assembly of TOM subunits. The biogenesis of the cytochrome c oxidase of the inner membrane involves a molecular circuit to adjust translation of mitochondrial-encoded core subunits to the availability of nuclear-encoded partner proteins. Thus, mitochondrial protein translocases not only import precursor proteins but can also support their assembly into functional complexes.

scholarly journals Protein import into mitochondria: the requirement for external ATP is precursor-specific whereas intramitochondrial ATP is universally needed for translocation into the matrix.

1994 ◽  
Vol 5 (4) ◽  
pp. 465-474 ◽  
Author(s):  
C Wachter ◽  
G Schatz ◽  
B S Glick
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Inner Membrane ◽  
In Vitro System ◽  
Mitochondrial Inner Membrane ◽  
Precursor Proteins ◽  
The Matrix

ATP is needed for the import of precursor proteins into mitochondria. However, the role of ATP and its site of action have been unclear. We have now investigated the ATP requirements for protein import into the mitochondrial matrix. These experiments employed an in vitro system that allowed ATP levels to be manipulated both inside and outside the mitochondrial inner membrane. Our results indicate that there are two distinct ATP requirements for mitochondrial protein import. ATP in the matrix is always needed for complete import of precursor proteins into this compartment, even when the precursors are presented to mitochondria in an unfolded conformation. In contrast, the requirement for external ATP is precursor-specific; depletion of external ATP strongly inhibits import of some precursors but has little or no effect with other precursors. A requirement for external ATP can often be overcome by denaturing the precursor with urea. We suggest that external ATP promotes the release of precursors from cytosolic chaperones, whereas matrix ATP drives protein translocation across the inner membrane.

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

scholarly journals Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

2021 ◽  
Vol 22 (9) ◽  
pp. 4359
Author(s):  
Sara Martín-Villanueva ◽  
Gabriel Gutiérrez ◽  
Dieter Kressler ◽  
Jesús de la Cruz
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosome Assembly ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Precursor Proteins ◽  
Assembly Factors ◽  
Ubiquitin Moiety ◽  
And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

scholarly journals Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process

2016 ◽  
Vol 27 (21) ◽  
pp. 3257-3272 ◽  
Author(s):  
Giovanna Cenini ◽  
Cornelia Rüb ◽  
Michael Bruderek ◽  
Wolfgang Voos
Keyword(s):  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Cellular Damage ◽  
Aβ Peptides ◽  
Mitochondrial Functions ◽  
Major Species ◽  
Protein Biogenesis ◽  
Precursor Proteins ◽  
Strong Inhibitory Effect

Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation of Aβ peptides and interference with mitochondrial functions. Nevertheless, the relevance of intracellular Aβ peptides in the pathophysiology of AD is controversial. Here we found that the two major species of Aβ peptides, in particular Aβ42, exhibited a strong inhibitory effect on the preprotein import reactions essential for mitochondrial biogenesis. However, Aβ peptides interacted only weakly with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. Aβ peptides significantly decreased the import competence of mitochondrial precursor proteins via an extramitochondrial coaggregation mechanism. Coaggregation and import inhibition were significantly stronger for the longer peptide Aβ42, correlating with its importance in AD pathology. Our results demonstrate that direct interference of aggregation-prone Aβ peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.

scholarly journals Mitochondrial Protein Import

2004 ◽  
Vol 279 (44) ◽  
pp. 45701-45707 ◽  
Author(s):  
Masatoshi Esaki ◽  
Hidaka Shimizu ◽  
Tomoko Ono ◽  
Hayashi Yamamoto ◽  
Takashi Kanamori ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import ◽  
Tom Complex ◽  
Membrane Complex ◽  
Cytosolic Side

Protein translocation across the outer mitochondrial membrane is mediated by the translocator called the TOM (translocase of the outer mitochondrial membrane) complex. The TOM complex possesses two presequence binding sites on the cytosolic side (thecissite) and on the intermembrane space side (thetranssite). Here we analyzed the requirement of presequence elements and subunits of the TOM complex for presequence binding to thecisandtranssites of the TOM complex. The N-terminal 14 residues of the presequence of subunit 9 of F0-ATPase are required for binding to thetranssite. The interaction between the presequence and thecissite is not sufficient to anchor the precursor protein to the TOM complex. Tom7 constitutes or is close to thetranssite and has overlapping functions with the C-terminal intermembrane space domain of Tom22 in the mitochondrial protein import.

scholarly journals How does the TOM complex mediate insertion of precursor proteins into the mitochondrial outer membrane?

2005 ◽  
Vol 171 (3) ◽  
pp. 419-423 ◽  
Author(s):  
Doron Rapaport
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Mitochondrial Outer Membrane ◽  
Outer Face ◽  
Outer Mitochondrial Membrane ◽  
Lipid Core ◽  
Tom Complex ◽  
Precursor Proteins

A multisubunit translocase of the outer mitochondrial membrane (TOM complex) mediates both the import of mitochondrial precursor proteins into the internal compartments of the organelle and the insertion of proteins residing in the mitochondrial outer membrane. The proposed β-barrel structure of Tom40, the pore-forming component of the translocase, raises the question of how the apparent uninterrupted β-barrel topology can be compatible with a role of Tom40 in releasing membrane proteins into the lipid core of the bilayer. In this review, I discuss insertion mechanisms of proteins into the outer membrane and present alternative models based on the opening of a multisubunit β-barrel TOM structure or on the interaction of outer membrane precursors with the outer face of the Tom40 β-barrel structure.

scholarly journals Mitochondrial carrier protein biogenesis: role of the chaperones Hsc70 and Hsp90

2009 ◽  
Vol 419 (2) ◽  
pp. 369-375 ◽  
Author(s):  
Vincenzo Zara ◽  
Alessandra Ferramosca ◽  
Philippe Robitaille-Foucher ◽  
Ferdinando Palmieri ◽  
Jason C. Young
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein 90 ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Carrier ◽  
Mitochondrial Inner Membrane ◽  
Heat Shock Cognate 70 ◽  
Protein Biogenesis ◽  
And Function ◽  
Import Receptor

Metabolite carrier proteins of the mitochondrial inner membrane share homology in their transmembrane domains, which also carries their targeting information. In addition, some carriers have cleavable presequences which are not essential for targeting, but have some other function before import. The cytosolic chaperones Hsc70 (heat-shock cognate 70) and Hsp90 (heat-shock protein 90) complex with carrier precursors and interact specifically with the Tom (translocase of the mitochondrial outer membrane) 70 import receptor to promote import. We analysed how the presequences of the PiC (phosphate carrier) and CIC (citrate carrier) relate to the mechanisms of chaperone-mediated import. Deletion of the PiC presequence reduced the efficiency of import but, notably, not by causing aggregation. Instead, binding of the protein to Hsc70 was reduced, as well as the dependence on Hsc70 for import. Hsp90 binding and function in import was not greatly affected, but it could not entirely compensate for the lack of Hsc70 interaction. Deletion of the presequence from CIC was shown to cause its aggregation, but had little effect on the contribution to import of either Hsc70 or Hsp90. The presequence of PiC, but not that of CIC, conferred Hsc70 binding to dihydrofolate reductase fusion proteins. In comparison, OGC (oxoglutarate carrier) lacks a presequence and was more soluble, though it is still dependent on both Hsc70 and Hsp90. We propose that carrier presequences evolved to improve targeting competence by different mechanisms, depending on physical properties of the precursors in the cytosolic targeting environment.

scholarly journals Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

2021 ◽  
Author(s):  
Anna M. Schlagowski ◽  
Katharina Knöringer ◽  
Sandrine Morlot ◽  
Ana Sáchez Vicente ◽  
Felix Boos ◽  
...  
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Model System ◽  
Model Systems ◽  
Aggregate Formation ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Polyq Protein ◽  
Rate Limiting

AbstractThe formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)

scholarly journals Amyloid β-peptides interfere with mitochondrial preprotein import competence by a co-aggregation process

2016 ◽  
Author(s):  
Giovanna Cenini ◽  
Cornelia Rüb ◽  
Michael Bruderek ◽  
Wolfgang Voos
Keyword(s):  
Mitochondrial Protein ◽  
Amyloid Β ◽  
Cellular Damage ◽  
Weakly Interact ◽  
Aβ Peptides ◽  
Mitochondrial Functions ◽  
Major Species ◽  
Protein Biogenesis ◽  
Precursor Proteins ◽  
Negative Effect

Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidences showed an intraneuronal accumulation of Aβ peptides and toxic effects on mitochondrial functions. Nevertheless, the relevance of intracellular Aβ peptides in the pathophysiology of AD remained controversial. Here, we found that the two major species of Aβ peptides, in particular Aβ42, exhibited a strong negative effect on the preprotein import reactions essential for mitochondrial protein biogenesis. However, Aβ peptides only weakly interact with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. Aβ peptides significantly decreased the import competence of mitochondrial precursor proteins through a specific co-aggregation mechanism. Co-aggregation and import inhibition were significantly stronger in case of the longer peptide Aβ42, correlating with its importance in AD pathology. Our results demonstrate that a direct interference of aggregation-prone Aβ peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.

scholarly journals Reinvestigation of the Requirement of Cytosolic ATP for Mitochondrial Protein Import

2004 ◽  
Vol 279 (19) ◽  
pp. 19464-19470 ◽  
Author(s):  
Takeyoshi Asai ◽  
Takashi Takahashi ◽  
Masatoshi Esaki ◽  
Shuh-ichi Nishikawa ◽  
Kenzo Ohtsuka ◽  
...  
Keyword(s):  
Protein Import ◽  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Mitochondrial Matrix ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Reticulocyte Lysate ◽  
Binding To Mitochondria

Protein import into mitochondria requires the energy of ATP hydrolysis inside and/or outside mitochondria. Although the role of ATP in the mitochondrial matrix in mitochondrial protein import has been extensively studied, the role of ATP outside mitochondria (external ATP) remains only poorly characterized. Here we developed a protocol for depletion of external ATP without significantly reducing the import competence of precursor proteins synthesizedin vitrowith reticulocyte lysate. We tested the effects of external ATP on the import of various precursor proteins into isolated yeast mitochondria. We found that external ATP is required for maintenance of the import competence of mitochondrial precursor proteins but that, once they bind to mitochondria, the subsequent translocation of presequence-containing proteins, but not the ADP/ATP carrier, proceeds independently of external ATP. Because depletion of cytosolic Hsp70 led to a decrease in the import competence of mitochondrial precursor proteins, external ATP is likely utilized by cytosolic Hsp70. In contrast, the ADP/ATP carrier requires external ATP for efficient import into mitochondria even after binding to mitochondria, a situation that is only partly attributed to cytosolic Hsp70.

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