Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level.

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Targeting Protein Degradation in Cancer Treatment

Current Chemical Biology ◽

10.2174/2212796814999200609131623 ◽

2020 ◽

Vol 14 ◽

Author(s):

Imane Bjij ◽

Ismail Hdoufane ◽

Mahmoud Soliman ◽

Menče Najdoska-Bogdanov ◽

Driss Cherqaoui

Keyword(s):

Protein Degradation ◽

Therapeutic Potential ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Cellular Protein ◽

Cellular Level ◽

Cancerous Cell ◽

Promising Target ◽

Anti Cancer ◽

Ubiquitin Proteasome

: The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

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Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Cells ◽

10.3390/cells10061552 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1552

Author(s):

Mariona Guitart-Mampel ◽

Pedro Urquiza ◽

Jordana I. Borges ◽

Anastasios Lymperopoulos ◽

Maria E. Solesio

Keyword(s):

Mitochondrial Dysfunction ◽

G Protein ◽

Adrenergic Receptor ◽

Cellular Level ◽

Cardiac Physiology ◽

Failing Heart ◽

Receptor Kinases ◽

And Function ◽

The Impact ◽

G Protein Coupled

The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

Journal of Clinical Oncology ◽

10.1200/jco.2012.44.0958 ◽

2013 ◽

Vol 31 (9) ◽

pp. 1231-1238 ◽

Cited By ~ 100

Author(s):

Lindsey N. Micel ◽

John J. Tentler ◽

Peter G. Smith ◽

Gail S. Eckhardt

Keyword(s):

Cell Cycle ◽

Anticancer Agents ◽

Cell Cycle Control ◽

Ubiquitin Proteasome System ◽

Cellular Regulation ◽

Ubiquitin Chain ◽

Key Enzyme ◽

Ubiquitin Proteasome ◽

Enzyme Families ◽

And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

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Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽

10.1371/journal.pgen.1010015 ◽

2022 ◽

Vol 18 (1) ◽

pp. e1010015

Author(s):

Cécile Ribot ◽

Cédric Soler ◽

Aymeric Chartier ◽

Sandy Al Hayek ◽

Rima Naït-Saïdi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Muscle Atrophy ◽

Late Onset ◽

Oral Treatment ◽

Ubiquitin Proteasome System ◽

Proteasome Activity ◽

Functional Study ◽

Oculopharyngeal Muscular Dystrophy ◽

Ubiquitin Proteasome ◽

And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

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Abstract 85: The AAA-ATPase p97 is a Critical Regulator of Cardiac Homeostasis

Circulation Research ◽

10.1161/res.121.suppl_1.85 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Matthew J Brody ◽

Michelle A Sargent ◽

Jeffery D Molkentin

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Complexes ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Dominant Negative ◽

Aaa Atpase ◽

And Function ◽

Thrombospondin 4

p97 is a AAA-ATPase that plays critical roles in a myriad of cellular protein quality control processes, including the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway that targets misfolded proteins in the ER for degradation in the cytosol by the ubiquitin proteasome system. Mutations in p97 cause a multisystem degenerative proteinopathy disorder called inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) that includes pathologies of the nervous system, skeletal muscle, bone, and heart. Previous studies in the laboratory into the mechanisms whereby thrombospondin 4 has its cardioprotective effects and enhanced ERAD activity identified p97 as a direct interacting partner. This observation suggested that p97 itself could be an important cardioprotective effector by benefiting protein quality control in the heart. To address this hypothesis here we generated cardiac-specific transgenic mice overexpressing wildtype p97 or a p97 K524A mutant with deficient ATPase activity, the latter of which functioned as a dominant negative. Mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop cardiomyopathy, upregulate several ERAD complex components, and have elevated levels of ubiquitinated proteins. Proteomics and immunoprecipitation assays identified overwhelming interactions between endogenous p97 and a number of interesting protein complexes that suggest unique functions for this protein in regulating protein quality control in the heart. The results and novel regulatory relationships will be presented, which suggests entirely unique pathways whereby p97 functions in the heart.

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

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20216701051 ◽

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.

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Noncoding RNA MaIL1 is an integral component of the TLR4–TRIF pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920393117 ◽

2020 ◽

Vol 117 (16) ◽

pp. 9042-9053 ◽

Cited By ~ 4

Author(s):

Marina Aznaourova ◽

Harshavardhan Janga ◽

Stephanie Sefried ◽

Andreas Kaufmann ◽

Jens Dorna ◽

...

Keyword(s):

Mammalian Cells ◽

Noncoding Rna ◽

Signal Transduction Pathway ◽

Ubiquitin Proteasome System ◽

Lavage Fluid ◽

Cellular Protein ◽

Type I ◽

Toll Like Receptor 4 ◽

Ubiquitin Proteasome ◽

Highly Correlated

RNA has been proposed as an important scaffolding factor in the nucleus, aiding protein complex assembly in the dense intracellular milieu. Architectural contributions of RNA to cytosolic signaling pathways, however, remain largely unknown. Here, we devised a multidimensional gradient approach, which systematically locates RNA components within cellular protein networks. Among a subset of noncoding RNAs (ncRNAs) cosedimenting with the ubiquitin–proteasome system, our approach unveiled ncRNA MaIL1 as a critical structural component of the Toll-like receptor 4 (TLR4) immune signal transduction pathway. RNA affinity antisense purification–mass spectrometry (RAP-MS) revealed MaIL1 binding to optineurin (OPTN), a ubiquitin-adapter platforming TBK1 kinase. MaIL1 binding stabilized OPTN, and consequently, loss of MaIL1 blunted OPTN aggregation, TBK1-dependent IRF3 phosphorylation, and type I interferon (IFN) gene transcription downstream of TLR4. MaIL1 expression was elevated in patients with active pulmonary infection and was highly correlated with IFN levels in bronchoalveolar lavage fluid. Our study uncovers MaIL1 as an integral RNA component of the TLR4–TRIF pathway and predicts further RNAs to be required for assembly and progression of cytosolic signaling networks in mammalian cells.

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To beat or not to beat: degradation of Cx43 imposes the heart rhythm

Biochemical Society Transactions ◽

10.1042/bst20150046 ◽

2015 ◽

Vol 43 (3) ◽

pp. 476-481 ◽

Cited By ~ 11

Author(s):

Tânia Martins-Marques ◽

Steve Catarino ◽

Carla Marques ◽

Paulo Pereira ◽

Henrique Girão

Keyword(s):

Ischemia Reperfusion ◽

Heart Rhythm ◽

Ubiquitin Proteasome System ◽

Cardiac Cells ◽

Main Function ◽

Metabolic Coupling ◽

Heart Ischemia ◽

Ubiquitin Proteasome ◽

And Function ◽

Fine Tune

The main function of the heart is to pump blood to the different parts of the organism, a task that is efficiently accomplished through proper electric and metabolic coupling between cardiac cells, ensured by gap junctions (GJ). Cardiomyocytes are the major cell population in the heart, and as cells with low mitotic activity, are highly dependent upon mechanisms of protein degradation. In the heart, both the ubiquitin-proteasome system (UPS) and autophagy participate in the fine-tune regulation of cardiac remodelling and function, either in physiological or pathological conditions. Indeed, besides controlling cardiac signalling pathways, UPS and autophagy have been implicated in the turnover of several myocardial proteins. Degradation of Cx43, the major ventricular GJ protein, has been associated to up-regulation of autophagy at the onset of heart ischemia and ischemia/reperfusion (I/R), which can have profound implications upon cardiac function. In this review, we present recent studies devoted to the involvement of autophagy and UPS in heart homoeostasis, with a particular focus on GJ.

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The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

The Journal of Cell Biology ◽

10.1083/jcb.200607084 ◽

2007 ◽

Vol 177 (2) ◽

pp. 205-210 ◽

Cited By ~ 61

Author(s):

Megan L. Landsverk ◽

Shumin Li ◽

Alex H. Hutagalung ◽

Ayaz Najafov ◽

Thorsten Hoppe ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Proteasome Inhibition ◽

Thick Filament ◽

Ubiquitin Proteasome System ◽

Loss Of Function ◽

Cellular Processes ◽

Ubiquitin Proteasome ◽

Myosin Motors ◽

And Function ◽

Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

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