Changes in the mitochondrial subproteome of mouse brain Rpn13-binding proteins induced by the neurotoxin MPTP and the neuroprotector isatin

2021 ◽  
Vol 67 (1) ◽  
pp. 51-65
Author(s):  
O.A. Buneeva ◽  
A.T. Kopylov ◽  
O.V. Gnedenko ◽  
M.V. Medvedeva ◽  
I.G. Kapitsa ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Binding Proteins ◽  
Functional Group ◽  
Neuroprotective Effect ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Proteins ◽  
Proteomic Profiling ◽  
Metabolism Regulation ◽  
Ubiquitin Proteasome ◽  
Biomedical Chemistry

Mitochondrial dysfunction and ubiquitin-proteasome system (UPS) failure contribute significantly to the development of Parkinson's disease (PD). The proteasome subunit Rpn13 located on the regulatory (19S) subparticle play an important role in the delivery of proteins, subjected to degradation, to the proteolytic (20S) part of proteasome. We have previously found several brain mitochondrial proteins specifically bound to Rpn13 (Buneeva et al. (2020) Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 14, 297-305). In this study we have investigated the effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroprotector isatin on the mitochondrial subproteome of Rpn13-binding proteins of the mouse brain. Administration of MPTP (30 mg/kg) to animals caused movement disorders typical of PD, while pretreatment with isatin (100 mg/kg, 30 min before MPTP) reduced their severity. At the same time, the injection of MPTP, isatin, or their combination (isatin + MPTP) had a significant impact on the total number and the composition of Rpn13-binding proteins. The injection of MPTP decreased the total number of Rpn13-binding proteins in comparison with control, and the injection of isatin prior to MPTP or without MPTP caused an essential increase in the number of Rpn13-binding proteins, mainly of the functional group of proteins participating in the protein metabolism regulation, gene expression, and differentiation. Selected biosensor validation confirmed the interaction of Rpn13 subunit of proteasome with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) revealed while proteomic profiling. The results obtained testify that under the conditions of experimental MPTP-induced parkinsonism the neuroprotective effect of isatin may be aimed at the interaction of mitochondria with the components of UPS.

scholarly journals Qualitative difference of mitochondrial subproteoms of brain RPN10- and RPN13-binding proteins

2020 ◽  
Vol 66 (2) ◽  
pp. 138-144
Author(s):  
O.A. Buneeva ◽  
A.T. Kopylov ◽  
A.E. Medvedev
Keyword(s):  
Binding Proteins ◽  
Qualitative Difference ◽  
High Specificity ◽  
Ubiquitin Proteasome System ◽  
Good Evidence ◽  
Mitochondrial Proteins ◽  
Regulatory Subunit ◽  
Target Proteins ◽  
Affinity Ligand ◽  
Subsequent Degradation

Good evidence exists that the ubiquitin-proteasome system (UPS) plays an important role in degradation of mitochondrial proteins and membrane proteins associated with mitochondria (MAM proteins). Mitochondria contain all components of the ubiquitin-conjugating system, which are necessary for the attachment of ubiquitin molecules to target proteins, subjected to subsequent degradation in proteasomes. An important stage in the delivery of proteins for proteolytic degradation in proteasomes is their interaction with ubiquitin receptors located on the regulatory subunit (19S) of the proteasome: the Rpn10 or Rpn13 subunit. These subunits make basically the same contribution to the subsequent translocation of target proteins to the core part of the proteasome. A comparative study of mouse brain mitochondrial subproteomes bound to Rpn10 and Rpn13 subunits revealed a high specificity of the repertoire of Rpn10 and Rpn13-binding proteins. Moreover, proteins, for which mitochondrial localization or association with mitochondrial membranes was previously shown, prevailed in the case of using the Rpn13 subunit as an affinity ligand (Rpn13-binding proteins). This suggests that Rpn10 and Rpn13 play different roles in the degradation of mitochondrial proteins and MAM.

Effect of affinity Sorbent on proteomic profiling of isatin-binding proteins of mouse brain

2012 ◽  
Vol 77 (11) ◽  
pp. 1326-1338 ◽  
Author(s):  
O. A. Buneeva ◽  
A. T. Kopylov ◽  
O. V. Tikhonova ◽  
V. G. Zgoda ◽  
A. E. Medvedev ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Binding Proteins ◽  
Proteomic Profiling ◽  
Affinity Sorbent

scholarly journals Mitochondrial ATP-Dependent Proteases—Biological Function and Potential Anti-Cancer Targets

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2020
Author(s):  
Yue Feng ◽  
Kazem Nouri ◽  
Aaron D. Schimmer
Keyword(s):  
Mitochondrial Membrane ◽  
Biological Function ◽  
Mitochondrial Respiratory Chain ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Novel Approaches ◽  
Novel Therapeutic

Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy.

Impact of Ubiquitination Signaling Pathway Modifications on Oral Carcinoma

2022 ◽  
Vol 2 (1) ◽  
pp. 1-6
Author(s):  
EFTHIMIOS KYRODIMOS ◽  
ARISTEIDIS CHRYSOVERGIS ◽  
NICHOLAS MASTRONIKOLIS ◽  
EVANGELOS TSIAMBAS ◽  
LOUKAS MANAIOS ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Broad Spectrum ◽  
Critical Role ◽  
Ubiquitin Proteasome System ◽  
Protein Targets ◽  
Metabolism Regulation ◽  
Substrate Protein ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation

Among intra-cellular homeostasis mechanisms, ubiquitination plays a critical role in protein metabolism regulation by degrading proteins via activating a broad spectrum of ubiquitin chains. In fact, ubiquitination and sumoylation signaling pathways are characterized by increased complexity regarding the molecules and their interactions. The Ubiquitin-Proteasome System (Ub-PS) recognizes and targets a broad spectrum of protein substrates. Ubiquitin conjugation modifies each substrate protein determining its biochemical fate (degradation). A major functional activity of Ub-PS is autophagy mechanism regulation. Interestingly, Ub-PS promotesall stages of bulk autophagy (initiation, execution, and termination). Autophagy is a crucial catabolic process that provides protein degradation and for this reason the interaction with Ub-PS is crucial. Furthermore, ubiquitination controls and regulates specific types of protein targets. Ub-PS is also involved in oxidative cellular stress and DNA damage response. Additionally, the functional role of Ub-PS in ribosome machinery regulation seems to be crucial. Concerning carcinogenesis, Ub-PS is involved in malignant disease development and progression by negatively affecting the corresponding TGF-B-, MEEK/MAPK/ERK-JNK- dependent signaling pathways. In the current review article, we describe the role of Ub-PSbiochemicalmodifications and alterations in oral squamous cell carcinoma (OSCC).

The effect of a neuroprotective dose of isatin or deprenyl to mice on the profile of brain isatin-binding proteins

2019 ◽  
Vol 65 (5) ◽  
pp. 407-417 ◽  
Author(s):  
O.A. Buneeva ◽  
I.G. Kapitsa ◽  
E.A. Ivanova ◽  
A.T. Kopylov ◽  
V.G. Zgoda ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Neuroprotective Effect ◽  
Proteomic Profiling ◽  
Pharmacological Activities ◽  
Dose Administration ◽  
Peripheral Tissues ◽  
Wide Range ◽  
Affinity Sorbent ◽  
The Brain

Isatin (indol-2,3-dione), an endogenous biofactor found in the brain, peripheral tissues and biological body fluids of humans and animals, exhibits a wide range of biological and pharmacological activities. They are realized via interaction with numerous isatin-binding proteins. Some of these proteins identified during proteomic profiling of the brain are involved in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl (selegiline), a pharmacological agent used for treatment of Parkinson's disease. In this study, we have investigated the effect of a single dose administration of isatin (100 mg/kg) and deprenyl (10 mg/kg) to mice on the profile of the brain isatin-binding proteins. Comparative proteomic analysis of brain isatin-binding proteins of mice treated with isatin or deprenyl resulted in identification of a representative group of proteins (n=200) sensitive to the administration of these substances. The change in the profile of isatin-binding proteins may be obviously attributed to accumulation of isatin and deprenyl in the brain and their interaction with target proteins; this prevents protein binding to the affinity sorbent. Thus identified brain isatin-binding proteins of the control animals obviously represent specific targets that interact directly with isatin (and also with deprenyl) in vivo. Isatin or deprenyl administered to animals interact with these proteins and thus inhibit their binding to the affinity sorbent (immobilized isatin analogue).

scholarly journals Transgenic Drosophila melanogaster model of metabolic disorders

2020 ◽  
Vol 4 (4) ◽  
pp. 811-817
Author(s):  
Thao Thi Phuong Dang ◽  
Linh My Dao ◽  
Anh Man Huynh ◽  
Dan Thi Hanh Vo
Keyword(s):  
Metabolic Syndrome ◽  
Drosophila Melanogaster ◽  
Beta Cells ◽  
Metabolic Disorders ◽  
Fruit Fly ◽  
Ubiquitin Proteasome System ◽  
Metabolism Regulation ◽  
Nutritional Conditions ◽  
Abnormal Metabolism ◽  
Ubiquitin Proteasome

Metabolic syndrome is a collection of disorders related to metabolisms such as obesity, lipid disorders, hyper/hypoglycemia, ... Metabolic syndrome can lead to cardiovascular diseases, strokes, and diabetes - the leading death causes in the world. In many cases, metabolic disorders are original by the redundant/ reduction of insulin- the most important hormone in metabolism regulation. Both of them are involved in beta-cells dysfunction. Many mechanisms related to this phenomenon has been approved, notably mitochondrial dysfunction and the Ubiquitin proteasome system impairment. UCH-L1 is a protein belonging to the Ubiquitin proteasome system and highly expressed in beta cells. Previous studies reported that decrease UCH-L1 function can alter metabolism and lead to b cell apoptosis under various nutritional conditions, however, the mechanism has not been clarified. In this study, we proposed a Drosophila melanogaster model that expresses many symptoms of metabolic syndrome, by knocking down dUCH (Drosophila homolog of UCH-L1) specifically in Insulin-producing cells. Our fruit fly model had abnormal metabolism, physiology, loss of insulinproducing cells, and mitochondria over-workload, similar to metabolic syndrome in humans. These results suggested that this model is suitable for further studies on the role of UCH-L1 in b cells, as well as a potential model in metabolism diseases' drug screening.

scholarly journals Egg activation triggers clearance of maternally deposited RNA binding proteins

2019 ◽  
Author(s):  
Michael Zavortink ◽  
Lauren N. Rutt ◽  
Svetlana Dzitoyeva ◽  
Chloe Barrington ◽  
Danielle Y. Bilodeau ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Ubiquitin Proteasome System ◽  
Egg Activation ◽  
List Type ◽  
Maternal Genome ◽  
Ubiquitin Conjugating Enzyme ◽  
Ubiquitin Proteasome ◽  
Conjugating Enzyme

SUMMARYThe maternal-to-zygotic transition (MZT) is a conserved step in animal development, where control is passed from the maternal genome to the zygotic one. Although the MZT is typically considered from its impact on the transcriptome, we previously found that three maternally deposited Drosophila RNA binding proteins (ME31B, Trailer Hitch [TRAL], and Cup) are also cleared during the MZT by unknown mechanisms. Here, we show that these proteins are degraded by the ubiquitin-proteasome system. Kondo, an E2 conjugating enzyme, and the E3 CTLH ligase are required for the destruction of ME31B, TRAL, and Cup. Importantly, despite occurring hours earlier, egg activation establishes the timer for clearance of these proteins by activating the Pan Gu kinase, which in turn stimulates translation of Kondo mRNA. In other words, egg activation triggers a series of regulatory events that culminate in the degradation of maternally deposited RNA binding proteins several hours later. Clearance of the maternal protein dowry thus appears to be a coordinated, but as-yet underappreciated, aspect of the MZT.HIGHLIGHTSDegradation of ME31B requires the PNG kinase, but not fertilizationThe ubiquitin-proteasome system degrades ME31B via CTLH E3 ligase and the UBC-E2H/Kondo ubiquitin-conjugating enzymeThe association of ME31B with the CTLH complex does not require PNG activityPNG kinase mediates the translational upregulation of Kondo at egg activation

scholarly journals Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization

2016 ◽  
Vol 113 (36) ◽  
pp. E5261-E5270 ◽  
Author(s):  
Won-Hee Song ◽  
Young-Joo Yi ◽  
Miriam Sutovsky ◽  
Stuart Meyers ◽  
Peter Sutovsky
Keyword(s):  
Protein Molecule ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Mitochondrial Proteins ◽  
Gamma Aminobutyric Acid ◽  
Receptor Associated Protein ◽  
Animal Development ◽  
Sequestosome 1 ◽  
Mammalian Sperm ◽  
Ubiquitin Proteasome

Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules.

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