scholarly journals Microautophagy – distinct molecular mechanisms handle cargoes of many sizes

2020 ◽  
Vol 133 (17) ◽  
pp. jcs246322 ◽  
Author(s):  
Sebastian Schuck
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Snare Proteins ◽  
Metabolic Adaptation ◽  
The Core ◽  
Range Of Functions ◽  
Fusion Type ◽  
Functional Versatility

ABSTRACTAutophagy is fundamental for cell and organismal health. Two types of autophagy are conserved in eukaryotes: macroautophagy and microautophagy. During macroautophagy, autophagosomes deliver cytoplasmic constituents to endosomes or lysosomes, whereas during microautophagy lytic organelles take up cytoplasm directly. While macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become clear that microautophagy has a broad range of functions in biosynthetic transport, metabolic adaptation, organelle remodeling and quality control. This Review discusses the selective and non-selective microautophagic processes known in yeast, plants and animals. Based on the molecular mechanisms for the uptake of microautophagic cargo into lytic organelles, I propose to distinguish between fission-type microautophagy, which depends on ESCRT proteins, and fusion-type microautophagy, which requires the core autophagy machinery and SNARE proteins. Many questions remain to be explored, but the functional versatility and mechanistic diversity of microautophagy are beginning to emerge.

scholarly journals Molecular Mechanisms and Regulation of Mammalian Mitophagy

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 38
Author(s):  
Vinay Choubey ◽  
Akbar Zeb ◽  
Allen Kaasik
Keyword(s):  
Quality Control ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Stress Protein ◽  
Antioxidant Defenses ◽  
Control Mechanisms ◽  
Mitochondrial Dna Damage ◽  
Cellular Environment ◽  
Rigorous Research ◽  
Functional Versatility

Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

scholarly journals Automation of dissolution tests

2003 ◽  
Vol 25 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Rolf Rolli
Keyword(s):  
Quality Control ◽  
In Vitro Dissolution ◽  
Pharmaceutical Companies ◽  
Dissolution Testing ◽  
Simultaneous Operation ◽  
Task Forces ◽  
The Core ◽  
Dissolution Tests ◽  
The 1960S

Dissolution testing of drug formulations was introduced in the 1960s and accepted by health regulatory authorities in the 1970s. Since then, the importance of dissolution has grown rapidly as have the number of tests and demands in quality-control laboratories. Recent research works lead to the development of in-vitro dissolution tests as replacements for human and animal bioequivalence studies. For many years, a lot of time and effort has been invested in automation of dissolution tests. There have been a number of in-house solutions from pharmaceutical companies and many have created task forces or even departments to develop automation. Robotic solutions with sequential operation were introduced as well as the simultaneous operation concept developed by SOTAX. Today, pharmaceutical companies focus their resources mainly on the core business and in-house engineering solutions that are very difficult to justify. Therefore, it is important to know the basic considerations in order to plan an automation concept and implement it together with a vendor.

scholarly journals A comparative analysis of differentially expressed mRNAs, miRNAs and circRNAs provides insights into the key genes involved in the high-altitude adaptation of yaks

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Qianyun Ge ◽  
Yongbo Guo ◽  
Wangshan Zheng ◽  
Yuan Cai ◽  
Xuebin Qi ◽  
...  
Keyword(s):  
High Altitude ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Differentially Expressed ◽  
The Tibetan Plateau ◽  
The Core ◽  
Processing Pathways ◽  
Genetic Information Processing ◽  
Altitude Adaptation ◽  
The Difference

Abstract Background Yaks that inhabit the Tibetan Plateau exhibit striking phenotypic and physiological differences from cattle and have adapted well to the extreme conditions on the plateau. However, the mechanisms used by these animals for the regulation of gene expression at high altitude are not fully understood. Results Here, we sequenced nine lung transcriptomes of yaks at altitudes of 3400, 4200 and 5000 m, and low-altitude Zaosheng cattle, which is a closely related species, served as controls. The analysis identified 21,764 mRNAs, 1377 circRNAs and 1209 miRNAs. By comparing yaks and cattle, 4975 mRNAs, 252 circRNAs and 75 miRNAs were identified differentially expressed. By comparing yaks at different altitudes, we identified 756 mRNAs, 64 circRNAs and 83 miRNAs that were differentially expressed (fold change ≥2 and P-value < 0.05). The pathways enriched in the mRNAs, circRNAs and miRNAs identified from the comparison of yaks and cattle were mainly associated with metabolism, including ‘glycosaminoglycan degradation’, ‘pentose and glucuronate interconversions’ and ‘flavone and flavonol biosynthesis’, and the mRNAs, circRNAs and miRNAs identified from the comparison of yaks at different altitude gradients were significantly enriched in metabolic pathways and immune and genetic information processing pathways. The core RNAs were identified from the mRNA-miRNA-circRNA networks constructed using the predominant differentially expressed RNAs. The core genes specific to the difference between yaks and cattle were associated with the endoplasmic reticulum and fat deposition, but those identified from the comparison among yaks at different altitude gradients were associated with maintenance of the normal biological functions of cells. Conclusions This study enhances our understanding of the molecular mechanisms involved in hypoxic adaptation in yaks and might contribute to improvements in the understanding and prevention of hypoxia-related diseases.

scholarly journals To catch a hijacker: abundance, evolution and genetic diversity of P4-like bacteriophage satellites

2021 ◽  
Vol 377 (1842) ◽  
Author(s):  
Jorge A. Moura de Sousa ◽  
Eduardo P. C. Rocha
Keyword(s):  
Escherichia Coli ◽  
Molecular Mechanisms ◽  
Core Genome ◽  
Mobile Genetic Elements ◽  
Abundance Distribution ◽  
Theme Issue ◽  
Genetic Elements ◽  
The Core ◽  
Antagonistic Interactions ◽  
Variable Genes

Bacteriophages (phages) are bacterial parasites that can themselves be parasitized by phage satellites. The molecular mechanisms used by satellites to hijack phages are sometimes understood in great detail, but the origins, abundance, distribution and composition of these elements are poorly known. Here, we show that P4-like elements are present in more than 30% of the genomes of Enterobacterales, and in almost half of those of Escherichia coli , sometimes in multiple distinct copies. We identified over 1000 P4-like elements with very conserved genetic organization of the core genome and a few hotspots with highly variable genes. These elements are never found in plasmids and have very little homology to known phages, suggesting an independent evolutionary origin. Instead, they are scattered across chromosomes, possibly because their integrases are often exchanged with other elements. The rooted phylogenies of hijacking functions are correlated and suggest longstanding coevolution. They also reveal broad host ranges in P4-like elements, as almost identical elements can be found in distinct bacterial genera. Our results show that P4-like phage satellites constitute a very distinct, widespread and ancient family of mobile genetic elements. They pave the way for studying the molecular evolution of antagonistic interactions between phages and their satellites. This article is part of the theme issue ‘The secret lives of microbial mobile genetic elements’.

scholarly journals Nitrogen starvation and stationary phase lipophagy have distinct molecular mechanisms

2020 ◽  
Author(s):  
Ravinder Kumar ◽  
Muhammad Arifur Rahman ◽  
Taras Y. Nazarko
Keyword(s):  
Lipid Droplets ◽  
Molecular Mechanisms ◽  
Nitrogen Starvation ◽  
S Phase ◽  
Carbon Limitation ◽  
Intracellular Lipid ◽  
Selective Autophagy ◽  
The Core ◽  
Vacuole Fusion ◽  
N Starvation

AbstractIn yeast, the selective autophagy of intracellular lipid droplets (LDs) or lipophagy can be induced by either nitrogen (N) starvation or carbon limitation (e.g. in the stationary (S) phase). We developed the yeast, Komagataella phaffii (formerly Pichia pastoris), as a new lipophagy model and compared the N-starvation and S-phase lipophagy in over 30 autophagy-related mutants using the Erg6-GFP processing assay. Surprisingly, two lipophagy pathways had hardly overlapping stringent molecular requirements. While the N-starvation lipophagy strictly depended on the core autophagic machinery (Atg1-Atg9, Atg18 and Vps15), vacuole fusion machinery (Vam7 and Ypt7) and vacuolar proteolysis (proteinases A and B), only Atg6 and proteinases A and B were essential for the S-phase lipophagy. The rest of the proteins were only partially required in the S-phase. Moreover, we isolated the prl1 (for positive regulator of lipophagy 1) mutant affected in the S-phase lipophagy but not N-starvation lipophagy. The prl1 defect was at a stage of delivery of the LDs from the cytoplasm to the vacuole further supporting mechanistically different nature of the two lipophagy pathways. Taken together, our results suggest that N-starvation and S-phase lipophagy have distinct molecular mechanisms.

Quality control loops: the core of integrated quality assurance

1991 ◽  
pp. 423-443
Author(s):  
Manfred Weck ◽  
Walter Eversheim ◽  
Wilfried König ◽  
Tilo Pfeifer
Keyword(s):  
Quality Control ◽  
Quality Assurance ◽  
Control Loops ◽  
The Core

scholarly journals Revisiting Bap Multidomain Protein: More Than Sticking Bacteria Together

2020 ◽  
Vol 11 ◽  
Author(s):  
Jaione Valle ◽  
Xianyang Fang ◽  
Iñigo Lasa
Keyword(s):  
Biofilm Formation ◽  
Core Genome ◽  
Current Knowledge ◽  
Surface Proteins ◽  
Structure And Properties ◽  
Diverse Range ◽  
The Core ◽  
Self Assembling ◽  
Abiotic Surfaces ◽  
Range Of Functions

One of the major components of the staphylococcal biofilm is surface proteins that assemble as scaffold components of the biofilm matrix. Among the different surface proteins able to contribute to biofilm formation, this review is dedicated to the Biofilm Associated Protein (Bap). Bap is part of the accessory genome of Staphylococcus aureus but orthologs of Bap in other staphylococcal species belong to the core genome. When present, Bap promotes adhesion to abiotic surfaces and induces strong intercellular adhesion by self-assembling into amyloid like aggregates in response to the levels of calcium and the pH in the environment. During infection, Bap enhances the adhesion to epithelial cells where it binds directly to the host receptor Gp96 and inhibits the entry of the bacteria into the cells. To perform such diverse range of functions, Bap comprises several domains, and some of them include several motifs associated to distinct functions. Based on the knowledge accumulated with the Bap protein of S. aureus, this review aims to summarize the current knowledge of the structure and properties of each domain of Bap and their contribution to Bap functionality.

scholarly journals Securing SNAREs for assembly

2020 ◽  
Vol 295 (30) ◽  
pp. 10136-10137
Author(s):  
Yongli Zhang ◽  
Jie Yang
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Snare Proteins ◽  
Membrane Tethering ◽  
Target Membrane

SNARE proteins are essential for exocytosis, mediating the fusion of vesicles with their target membrane. Tethering factors play a key role in chaperoning SNARE assembly; however, the underlying molecular mechanisms are not well-understood. Here, Travis et al. report two crystal structures of a yeast tethering factor, the Dsl1 complex, bound with two SNARE proteins, revealing new insights into how tethering factors bridge vesicles to target membranes, recruit multiple SNARE proteins, trigger their conformational changes, and facilitate SNARE assembly.

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