scholarly journals MITOCHONDRIAL PROTEIN PROFILE AND ITS ROLE IN PATHOLOGIC PROCESSES

2013 ◽  
Vol 12 (3) ◽  
pp. 5-17
Author(s):  
Ye. A. Kosterina ◽  
I. I. Kozenkov ◽  
V. A. Kasymov ◽  
P. A. Kamensky ◽  
I. N. Dominova ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Profile ◽  
Mitochondrial Protein ◽  
Proteome Profiling ◽  
Mitochondrial Proteome ◽  
Mitochondrial Functions ◽  
Precursor Proteins ◽  
Real Size ◽  
Pathologic Processes

Mitochondria import hundreds of different precursor proteins from the cytosol, and only 13 proteins are encoded by mtDNA itself. Recent investigations demonstrated real size of mitochondrial proteome and complexity of their functions There are many methods using for mitochondrial proteome profiling, that help to understand a molecular mechanisms of mitochondrial functions and identify the causes of disruptions that lead to different disorders. In this review we discuss a recent data in the field of mitochondrial proteomics.

scholarly journals Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 674
Author(s):  
Francesco Capriglia ◽  
Francesca Rizzo ◽  
Giuseppe Petrosillo ◽  
Veronica Morea ◽  
Giulia d’Amati ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Mitochondrial Protein Synthesis ◽  
Mitochondrial Translation ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Mitochondrial Functions ◽  
Carboxy Terminal

The m.3243A>G mutation within the mitochondrial mt-tRNALeu(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

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 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 A high-density human mitochondrial proximity interaction network

2020 ◽  
Author(s):  
Hana Antonicka ◽  
Zhen-Yuan Lin ◽  
Alexandre Janer ◽  
Woranontee Weraarpachai ◽  
Anne-Claude Gingras ◽  
...  
Keyword(s):  
High Resolution ◽  
Correlation Analysis ◽  
Mitochondrial Protein ◽  
Interaction Network ◽  
Mitochondrial Proteins ◽  
Site Formation ◽  
List Type ◽  
Mitochondrial Proteome ◽  
Mitochondrial Functions ◽  
The Matrix

SummaryWe used BioID, a proximity-dependent biotinylation assay, to interrogate 100 mitochondrial baits from all mitochondrial sub-compartments to create a high resolution human mitochondrial proximity interaction network. We identified 1465 proteins, producing 15626 unique high confidence proximity interactions. Of these, 528 proteins were previously annotated as mitochondrial, nearly half of the mitochondrial proteome defined by Mitocarta 2.0. Bait-bait analysis showed a clear separation of mitochondrial compartments, and correlation analysis among preys across all baits allowed us to identify functional clusters involved in diverse mitochondrial functions, and to assign uncharacterized proteins to specific modules. We demonstrate that this analysis can assign isoforms of the same mitochondrial protein to different mitochondrial sub-compartments, and show that some proteins may have multiple cellular locations. Outer membrane baits showed specific proximity interactions with cytosolic proteins and proteins in other organellar membranes, suggesting specialization of proteins responsible for contact site formation between mitochondria and individual organelles. This proximity network will be a valuable resource for exploring the biology of uncharacterized mitochondrial proteins, the interactions of mitochondria with other cellular organelles, and will provide a framework to interpret alterations in sub-mitochondrial environments associated with mitochondrial disease.Bullet pointsWe created a high resolution human mitochondrial protein proximity map using BioIDBait-bait analysis showed that the map has sub-compartment resolution and correlation analysis of preys identified functional clusters and assigned proteins to specific modulesWe identified isoforms of matrix and IMS proteins with multiple cellular localizations and an endonuclease that localizes to both the matrix and the OMMOMM baits showed specific interactions with non-mitochondrial proteins reflecting organellar contact sites and protein dual localization

scholarly journals Increased supraorganization of respiratory complexes is a dynamic multistep remodelling in response to proteostasis stress

2020 ◽  
Vol 133 (18) ◽  
pp. jcs248492
Author(s):  
Shivali Rawat ◽  
Suparna Ghosh ◽  
Debodyuti Mondal ◽  
Valpadashi Anusha ◽  
Swasti Raychaudhuri
Keyword(s):  
Complex I ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Complex Iii ◽  
Complex Iv ◽  
Mitochondrial Proteome ◽  
Respiratory Complexes ◽  
The Core ◽  
Mitochondrial Functions ◽  
Folding Pathways

ABSTRACTProteasome-mediated degradation of misfolded proteins prevents aggregation inside and outside mitochondria. But how do cells safeguard the mitochondrial proteome and mitochondrial functions despite increased aggregation during proteasome inactivation? Here, using a novel two-dimensional complexome profiling strategy, we report increased supraorganization of respiratory complexes (RCs) in proteasome-inhibited cells that occurs simultaneously with increased pelletable aggregation of RC subunits inside mitochondria. Complex II (CII) and complex V (CV) subunits are increasingly incorporated into oligomers. Complex I (CI), complex III (CIII) and complex IV (CIV) subunits are engaged in supercomplex formation. We unravel unique quinary states of supercomplexes during early proteostatic stress that exhibit plasticity and inequivalence of constituent RCs. The core stoichiometry of CI and CIII is preserved, whereas the composition of CIV varies. These partially disintegrated supercomplexes remain functionally competent via conformational optimization. Subsequently, increased stepwise integration of RC subunits into holocomplexes and supercomplexes re-establishes steady-state stoichiometry. Overall, the mechanism of increased supraorganization of RCs mimics the cooperative unfolding and folding pathways for protein folding, but is restricted to RCs and is not observed for any other mitochondrial protein complexes.This article has an associated First Person interview with the first author of the paper.

scholarly journals Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Daniela Criscuolo ◽  
Rosario Avolio ◽  
Danilo Swann Matassa ◽  
Franca Esposito
Keyword(s):  
Protein Synthesis ◽  
De Novo ◽  
Mitochondrial Protein ◽  
Mrna Translation ◽  
Cellular Transformation ◽  
Future Research ◽  
Mitochondrial Proteome ◽  
Metabolic Functions ◽  
Mitochondrial Functions ◽  
Metabolic Remodeling

Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.

scholarly journals Protein Quality Control at the Mitochondrial Surface

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabian den Brave ◽  
Arushi Gupta ◽  
Thomas Becker
Keyword(s):  
Quality Control ◽  
Outer Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Outer Membrane Proteins ◽  
Tom Complex ◽  
Cellular Environment ◽  
Mitochondrial Functions ◽  
Precursor Proteins

Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

scholarly journals Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain

2021 ◽  
Vol 22 (15) ◽  
pp. 8325
Author(s):  
Paola Zanfardino ◽  
Stefano Doccini ◽  
Filippo M. Santorelli ◽  
Vittoria Petruzzella
Keyword(s):  
Human Brain ◽  
Basic Function ◽  
Mitochondrial Proteome ◽  
Novel Proteins ◽  
Mitochondrial Functions ◽  
Organ Specific ◽  
Oxphos System ◽  
Mitochondrial Defects ◽  
Energy Dependent ◽  
The Brain

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

Unstable mitochondrial DNA in natural-death nuclear mutants of Neurospora crassa

1989 ◽  
Vol 9 (10) ◽  
pp. 4259-4264
Author(s):  
B L Seidel-Rogol ◽  
J King ◽  
H Bertrand
Keyword(s):  
Neurospora Crassa ◽  
Mitochondrial Protein ◽  
Nuclear Gene ◽  
Recessive Mutation ◽  
Natural Death ◽  
Mitochondrial Ribosomes ◽  
Large Deletions ◽  
Group I ◽  
Mitochondrial Functions ◽  
Mitochondrial Chromosome

The natural-death mutant of Neurospora crassa has an accelerated senescence phenotype caused by a recessive mutation, nd, in a nuclear gene that is located in linkage group I. An examination of mitochondrial functions, however, revealed that the mutant has phenotypic and molecular defects similar to those commonly associated with maternally transmitted fungal senescence syndromes, including (i) deficiencies in cytochromes aa3 and b; (ii) a deficit in small subunits of mitochondrial ribosomes, and hence defective mitochondrial protein synthesis; and (iii) accumulation of gross rearrangements, including large deletions, in the mitochondrial chromosome of vegetatively propagated cells. These traits indicate that the nd+ allele codes for a function that is essential for stable maintenance of the mitochondrial chromosome, possibly a protein involved in replication, repair, or recombination.

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