scholarly journals The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 253 ◽  
Author(s):  
Wolfgang Voos ◽  
Karen Pollecker
Keyword(s):  
Mammalian Cells ◽  
Protein Quality ◽  
Proteolytic Enzymes ◽  
Mitochondrial Gene ◽  
Protective Action ◽  
Stress Conditions ◽  
Endogenous Protein ◽  
The Matrix ◽  
Beaten Track ◽  
Protein Quality Control System

To maintain organellar function, mitochondria contain an elaborate endogenous protein quality control system. As one of the two soluble energy-dependent proteolytic enzymes in the matrix compartment, the protease Lon is a major component of this system, responsible for the degradation of misfolded proteins, in particular under oxidative stress conditions. Lon defects have been shown to negatively affect energy production by oxidative phosphorylation but also mitochondrial gene expression. In this review, recent studies on the role of Lon in mammalian cells, in particular on its protective action under diverse stress conditions and its relationship to important human diseases are summarized and commented.

scholarly journals M1-linked ubiquitination facilitates NF-κB activation during sterile inflammation

2021 ◽  
Author(s):  
Anna Aalto ◽  
Gabriela Martínez-Chacón ◽  
Nadezhda Tsyganova ◽  
Joose Kreutzer ◽  
Pasi Kallio ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Mammalian Cells ◽  
Inflammatory Diseases ◽  
Protective Action ◽  
Nuclear Factor Κb ◽  
Stress Conditions ◽  
Sterile Inflammation ◽  
Low Oxygen ◽  
Imd Pathway ◽  
Iκb Kinase

Methionine 1 (M1)-linked ubiquitination plays a key role in the regulation of inflammatory nuclear factor-κB (NF-κB) signalling and is important for clearance of pathogen infection in Drosophila melanogaster. M1-linked ubiquitin (M1-Ub) chains are assembled by the linear ubiquitin E3 ligase (LUBEL) in flies. Here, we have studied the role of LUBEL in sterile inflammation induced by different types of cellular stresses. We have found that LUBEL catalyses formation of M1-Ub chains in response to hypoxic, oxidative and mechanical stress conditions. LUBEL is shown to be important for flies to survive low oxygen conditions and paraquat-induced oxidative stress. This protective action seems to be driven by stress-induced activation of the NF-κB transcription factor Relish via the Immune deficiency (Imd) pathway. In addition to LUBEL, the intracellular mediators of Relish activation, including the Drosophila inhibitor of apoptosis (IAP) Diap2, the IκB kinase γ (IKKγ) Kenny and the initiator caspase Death-related ced-3/Nedd2-like protein (Dredd), but not the membrane receptor peptidoglycan recognition protein (PGRP)-LC, are shown to be required for sterile inflammatory response and survival. Finally, we showed that the stress-induced upregulation of M1-Ub chains in response to hypoxia, oxidative and mechanical stress is also induced in mammalian cells. Taken together, our results suggest that M1-Ub chains are important for NF-κB signalling in inflammation induced by stress conditions often observed in chronic inflammatory diseases and cancer.

scholarly journals Heparan sulfate is a clearance receptor for aberrant extracellular proteins

2020 ◽  
Vol 219 (3) ◽  
Author(s):  
Eisuke Itakura ◽  
Momoka Chiba ◽  
Takeshi Murata ◽  
Akira Matsuura
Keyword(s):  
Quality Control ◽  
Heparan Sulfate ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Amyloid Β ◽  
Degradation Pathway ◽  
Extracellular Proteins ◽  
Amyloid Β Peptide ◽  
Biochemical Analyses ◽  
Protein Quality Control System

The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor. Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin–HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.

scholarly journals LONP1 Regulates Mitochondrial Accumulations of HMGB1 and Caspase-3 in CA1 and PV Neurons Following Status Epilepticus

2021 ◽  
Vol 22 (5) ◽  
pp. 2275
Author(s):  
Ji-Eun Kim ◽  
Hana Park ◽  
Tae-Hyun Kim ◽  
Tae-Cheon Kang
Keyword(s):  
Status Epilepticus ◽  
Caspase 3 ◽  
Protein Quality ◽  
Mitochondrial Gene ◽  
High Mobility ◽  
Ca1 Neurons ◽  
Neuronal Viability ◽  
Mammalian Mitochondria ◽  
Protein Quality Control System ◽  
Active Caspase

Lon protease 1 (LONP1) is a highly conserved serine peptidase that plays an important role in the protein quality control system in mammalian mitochondria. LONP1 catalyzes the degradation of oxidized, dysfunctional, and misfolded matrix proteins inside mitochondria and regulates mitochondrial gene expression and genome integrity. Therefore, LONP1 is up-regulated and suppresses cell death in response to oxidative stress, heat shock, and nutrient starvation. On the other hand, translocation of high mobility group box 1 (HMGB1) and active caspase-3 into mitochondria is involved in apoptosis of parvalbumin (PV) cells (one of the GABAergic interneurons) and necrosis of CA1 neurons in the rat hippocampus, respectively, following status epilepticus (SE). In the present study, we investigated whether LONP1 may improve neuronal viability to prevent or ameliorate translocation of active caspase-3 and HMGB1 in mitochondria within PV and CA1 neurons. Following SE, LONP1 expression was up-regulated in mitochondria of PV and CA1 neurons. LONP1 knockdown deteriorated SE-induced neuronal death with mitochondrial accumulation of active caspase-3 and HMGB1 in PV cells and CA1 neurons, respectively. LONP1 knockdown did not affect the aberrant mitochondrial machinery induced by SE. Therefore, our findings suggest, for the first time, that LONP1 may contribute to the alleviation of mitochondrial overloads of active caspase-3 and HMGB1, and the maintenance of neuronal viability against SE.

A manganese oxide nanozyme prevents the oxidative damage of biomolecules without affecting the endogenous antioxidant system

Nanoscale ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 3855-3863 ◽  
Author(s):  
Namrata Singh ◽  
Mohammed Azharuddin Savanur ◽  
Shubhi Srivastava ◽  
Patrick D'Silva ◽  
Govindasamy Mugesh
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Manganese Oxide ◽  
Antioxidant System ◽  
Mammalian Cells ◽  
Redox State ◽  
Stress Conditions ◽  
System P ◽  
Endogenous Antioxidant ◽  
Antioxidant Machinery

Multi-enzyme mimetic Mn3O4 nanoflowers (Mp) modulate the redox state of mammalian cells without altering the cellular antioxidant machinery under oxidative stress conditions.

scholarly journals Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria

2019 ◽  
Vol 47 (14) ◽  
pp. 7502-7517 ◽  
Author(s):  
Anna V Kotrys ◽  
Dominik Cysewski ◽  
Sylwia D Czarnomska ◽  
Zbigniew Pietras ◽  
Lukasz S Borowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Mitochondrial Gene ◽  
Binding Activity ◽  
Stress Conditions ◽  
Mitochondrial Rna ◽  
Mitochondrial Gene Expression ◽  
Compensatory Mechanisms ◽  
Temporary Reduction ◽  
Mitochondrial Transcription

AbstractMaintenance of mitochondrial gene expression is crucial for cellular homeostasis. Stress conditions may lead to a temporary reduction of mitochondrial genome copy number, raising the risk of insufficient expression of mitochondrial encoded genes. Little is known how compensatory mechanisms operate to maintain proper mitochondrial transcripts levels upon disturbed transcription and which proteins are involved in them. Here we performed a quantitative proteomic screen to search for proteins that sustain expression of mtDNA under stress conditions. Analysis of stress-induced changes of the human mitochondrial proteome led to the identification of several proteins with poorly defined functions among which we focused on C6orf203, which we named MTRES1 (Mitochondrial Transcription Rescue Factor 1). We found that the level of MTRES1 is elevated in cells under stress and we show that this upregulation of MTRES1 prevents mitochondrial transcript loss under perturbed mitochondrial gene expression. This protective effect depends on the RNA binding activity of MTRES1. Functional analysis revealed that MTRES1 associates with mitochondrial RNA polymerase POLRMT and acts by increasing mitochondrial transcription, without changing the stability of mitochondrial RNAs. We propose that MTRES1 is an example of a protein that protects the cell from mitochondrial RNA loss during stress.

Proteolytic enzymes and trypsin inhibitors of higher plants under stress conditions

2008 ◽  
Vol 34 (3) ◽  
pp. 318-322 ◽  
Author(s):  
V. I. Domash ◽  
T. P. Sharpio ◽  
S. A. Zabreiko ◽  
T. F. Sosnovskaya
Keyword(s):  
Higher Plants ◽  
Proteolytic Enzymes ◽  
Trypsin Inhibitors ◽  
Stress Conditions

Adult human chondrocytes cultured in alginate form a matrix similar to native human articular cartilage

1996 ◽  
Vol 271 (3) ◽  
pp. C742-C752 ◽  
Author(s):  
H. J. Hauselmann ◽  
K. Masuda ◽  
E. B. Hunziker ◽  
M. Neidhart ◽  
S. S. Mok ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cell Sorting ◽  
Proteolytic Enzymes ◽  
Alginate Beads ◽  
Human Chondrocytes ◽  
Human Articular Cartilage ◽  
Adult Human ◽  
The Matrix ◽  
Matrix Compartment ◽  
Associated Matrix

The matrix formed by adult human chondrocytes in alginate beads is composed of two compartments: a thin rim of cell-associated matrix that corresponds to the pericellular and territorial matrix of articular cartilage and a more abundant further-removed matrix, the equivalent of the interterritorial matrix in the tissue. On day 30 of culture, the relative and absolute volumes occupied by the cells and each of the two matrix compartments in the beads were nearly identical to those in native articular cartilage. Furthermore, the concentration of aggrecan in the cell-associated matrix was similar to that in adult human articular cartilage and was approximately 40-fold higher than in the further removed matrix compartment. Fluorescence-activated cell sorting revealed that the cell-associated matrix was built on the cell membrane in part via interactions between hyaluronic acid and CD44-like receptors. Approximately 25% of the aggrecan molecules synthesized by the chondrocytes during a 4-h pulse in the presence of [35S]sulfate on day 9 of culture were retained in the cell-associated matrix where they turned over with a half-life (t1/2) = 29 days. Most [35S]aggrecan molecules reached the further removed matrix compartment where they turned over much more slowly (t1/2 > 100 days). These results add support to the contention that aggrecan molecules residing in the pericellular and territorial areas of the adult human articular cartilage matrix are more susceptible to degradation by proteolytic enzymes synthesized by the chondrocytes than those that inhabit the interterritorial areas further removed from the cells.

scholarly journals Pathogenesis of shigella diarrhea. VII. Evidence for a cell membrane toxin receptor involving β1 {arrow} 4-linked N-acetyl-D-glucosamine oligomers

1977 ◽  
Vol 146 (2) ◽  
pp. 535-546 ◽  
Author(s):  
GT Keusch ◽  
M Jacewicz
Keyword(s):  
Cell Membrane ◽  
Cholera Toxin ◽  
Liver Cell ◽  
Hela Cells ◽  
Mammalian Cells ◽  
Cell Membranes ◽  
Proteolytic Enzymes ◽  
Cell Monolayer ◽  
Toxin Receptor ◽  
Toxin Uptake

The binding of ShigeUa dysenteriae 1 cytotoxin to HeLa cells in culture and to isolated rat liver cell membranes was studied by means of an indirect consumption assay of toxicity from the medium, or by determination of cytotoxicity to the HeLa cell monolayer. Both liver cell membranes and HeLa cells removed toxicity from the medium during incubation, in contrast to WI-38 and Y-1 mouse adrenal tumor cells, both of which neither bound nor were affected by the toxin. Uptake of toxin was directly related to concentration of membranes added, time,and temperature, and indirectly related to the ionic strength of the buffer used. The chemical nature of the membrane receptor was characterized by using three principal approaches: (a) enzymatic sensitivity; (b) competitive inhibition and (c) receptor blockade studies. The receptor was destroyed by proteolytic enzymes, phospholipases (which markedly altered the gross appearance of the membrane preparation) and by lysozyme, but not by a variety of other enzymes. Of 28 carbohydrate and glycoprotein haptens studied, including cholera toxin and ganglioside, only the chitin oligosaccharide lysozyme substrates, per N-acetylated chitotriose, chitotetraose, and chitopentaose were effective competitive inhibitors. Greatest inhibition was found with the trimer, N, N', N" triacetyl chitotriose. Of three lectins studied as possible receptor blockers, including phytohemagglutinin, concanavalin A, and wheat germ agglutinin, only the latter, which is known to possess specific binding affinity for N, N', N" triacetyl chitotriose, was able to block toxin uptake. Evidence from all three approaches indicate, therefore, existence of a glycoprotein toxin receptor on mammalian cells, with involvement of oligomeric β1{arrow}4-1inked N-acetyl glucosamine in the receptor. This receptor is clearly distinct from the G(M1) ganglioside thought to be involved in the binding of cholera toxin to the cell membrane of a variety of cell types susceptible to its action.

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