scholarly journals A Genomewide Screen Reveals a Role of Mitochondria in Anaerobic Uptake of Sterols in Yeast

2006 ◽  
Vol 17 (1) ◽  
pp. 90-103 ◽  
Author(s):  
Sonja Reiner ◽  
Delphine Micolod ◽  
Günther Zellnig ◽  
Roger Schneiter
Keyword(s):  
Mitochondrial Function ◽  
Membrane Trafficking ◽  
Intracellular Transport ◽  
Unsaturated Fatty Acids ◽  
Cell Fractionation ◽  
Anaerobic Conditions ◽  
Cellular Functions ◽  
Sterol Uptake ◽  
Mitochondrial Functions ◽  
Wide Range

The mechanisms that govern intracellular transport of sterols in eukaryotic cells are not well understood. Saccharomyces cerevisiae is a facultative anaerobic organism that becomes auxotroph for sterols and unsaturated fatty acids in the absence of oxygen. To identify pathways that are required for uptake and transport of sterols, we performed a systematic screen of the yeast deletion mutant collection for genes that are required for growth under anaerobic conditions. Of the ∼4800 nonessential genes represented in the deletion collection, 37 were essential for growth under anaerobic conditions. These affect a wide range of cellular functions, including biosynthetic pathways for certain amino acids and cofactors, reprogramming of transcription and translation, mitochondrial function and biogenesis, and membrane trafficking. Thirty-three of these mutants failed to grow on lipid-supplemented media when combined with a mutation in HEM1, which mimics anaerobic conditions in the presence of oxygen. Uptake assays with radio- and fluorescently labeled cholesterol revealed that 17 of the 33 mutants strongly affect uptake and/or esterification of exogenously supplied cholesterol. Examination of the subcellular distribution of sterols in these uptake mutants by cell fractionation and fluorescence microscopy indicates that some of the mutants block incorporation of cholesterol into the plasma membrane, a presumably early step in sterol uptake. Unexpectedly, the largest class of uptake mutants is affected in mitochondrial functions, and many of the uptake mutants show electron-dense mitochondrial inclusions. These results indicate that a hitherto uncharacterized mitochondrial function is required for sterol uptake and/or transport under anaerobic conditions and are discussed in light of the fact that mitochondrial import of cholesterol is required for steroidogenesis in vertebrate cells.

Sterol and lipid trafficking in mammalian cells

2006 ◽  
Vol 34 (3) ◽  
pp. 335-339 ◽  
Author(s):  
F.R. Maxfield ◽  
M. Mondal
Keyword(s):  
Membrane Trafficking ◽  
Mammalian Cells ◽  
Intracellular Transport ◽  
Vesicular Transport ◽  
Cholesterol Content ◽  
Cellular Functions ◽  
Lipid Trafficking ◽  
Sterol Transport ◽  
A Cell ◽  
Asymmetrically Distributed

The pathways involved in the intracellular transport and distribution of lipids in general, and sterols in particular, are poorly understood. Cholesterol plays a major role in modulating membrane bilayer structure and important cellular functions, including signal transduction and membrane trafficking. Both the overall cholesterol content of a cell, as well as its distribution in specific organellar membranes are stringently regulated. Several diseases, many of which are incurable at present, have been characterized as results of impaired cholesterol transport and/or storage in the cells. Despite their importance, many fundamental aspects of intracellular sterol transport and distribution are not well understood. For instance, the relative roles of vesicular and non-vesicular transport of cholesterol have not yet been fully determined, nor are the non-vesicular transport mechanisms well characterized. Similarly, whether cholesterol is asymmetrically distributed between the two leaflets of biological membranes, and if so, how this asymmetry is maintained, is poorly understood. In this review, we present a summary of the current understanding of these aspects of intracellular trafficking and distribution of lipids, and more specifically, of sterols.

LRRK2 at the Crossroad Between Autophagy and Microtubule Trafficking

2016 ◽  
Vol 23 (1) ◽  
pp. 16-26 ◽  
Author(s):  
A. Raquel Esteves ◽  
Sandra M. Cardoso
Keyword(s):  
Mitochondrial Function ◽  
Membrane Domains ◽  
Common Variants ◽  
Cellular Functions ◽  
Large Protein ◽  
Knock Out ◽  
Wide Range ◽  
Lrrk2 Gene ◽  
Cytoskeletal Dynamics ◽  
Specific Membrane

Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson’s disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.

Lysosphingolipids and mitochondrial function. II. Deleterious effects of sphingosylphosphorylcholine

1988 ◽  
Vol 66 (12) ◽  
pp. 1322-1332 ◽  
Author(s):  
Paula M. Strasberg ◽  
John W. Callahan
Keyword(s):  
Mitochondrial Function ◽  
Direct Interaction ◽  
Lysosomal Storage Diseases ◽  
Mitochondrial Atpase ◽  
Lysosomal Storage ◽  
Mitochondrial Membranes ◽  
Cellular Functions ◽  
Partial Explanation ◽  
Atpase Reaction ◽  
Wide Range

Psychosine, sphingosylphosphorylcholine (52–104 μM), and other glycosphingolipids stimulate mitochondrial respiration (up to 500%) and inhibit oxidative phosphorylation to varying degrees. Above 104 μM these functions as well as uptake of Ca2+ are prevented. At 104 μM sphingosylphosphorylcholine inhibits the mitochondrial ATPase reaction in submitochondrial particles by 48%. Both sphingosylphosphorylcholine and psychosine enhance the active phosphate-dependent swelling of mitochondria. Passive swelling occurs in the presence of rotenone (when swelling does not normally occur) and under hypotonic conditions. A direct interaction of sphingosylphosphorylcholine with membranes is demonstrated by a discharge of the proton gradient across mitochondrial membranes, hemolysis of red blood cells, and binding to inner and outer mitochondrial membranes. Thus lysosphingolipids bind strongly to mitochondrial membranes and markedly alter mitochondrial function. This alteration would affect the ATP levels, thereby altering a wide range of ATP-dependent cellular functions. These results offer a partial explanation for the pathogenesis of representative lysosomal storage diseases.

scholarly journals Saccharomyces cerevisiae, a model to study sterol uptake and transport in eukaryotes

2005 ◽  
Vol 33 (5) ◽  
pp. 1186-1188 ◽  
Author(s):  
S. Reiner ◽  
D. Micolod ◽  
R. Schneiter
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Unsaturated Fatty Acids ◽  
Eukaryotic Cells ◽  
Lipid Uptake ◽  
Anaerobic Conditions ◽  
Transport Pathway ◽  
Uptake And Transport ◽  
Mutant Collection

The molecular mechanisms that govern intracellular transport of sterols in eukaryotic cells are only poorly understood. Saccharomyces cerevisiae is a facultative anaerobic organism that requires supplementation with unsaturated fatty acids and sterols to grow in the absence of oxygen, as the synthesis of these lipids requires molecular oxygen. The fact that yeast grows well under anaerobic conditions indicates that lipid uptake is rapid and efficient. To identify components in this lipid uptake and transport pathway, we screened the yeast mutant collection for genes that are essential under anaerobic conditions. Out of the approx. 4800 non-essential genes represented in the mutant collection, 37 were required for growth under anaerobic conditions. Uptake assays using radiolabelled cholesterol revealed that 16 of these genes are required for cholesterol uptake/transport and esterification. Further characterization of the precise role of these genes is likely to advance our understanding of this elusive pathway in yeast and may prove to be relevant to understand sterol homoeostasis in higher eukaryotic cells.

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Zhongyuan Piao ◽  
Lin Song ◽  
Lifen Yao ◽  
Limei Zhang ◽  
Yichan Lu
Keyword(s):  
Energy Metabolism ◽  
Cytochrome C ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Mitochondrial Functions ◽  
Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

scholarly journals When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Disease Development ◽  
Pathological Conditions ◽  
Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

scholarly journals Profiling of human burned bones: oxidising versus reducing conditions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. P. M. Marques ◽  
D. Gonçalves ◽  
A. P. Mamede ◽  
T. Coutinho ◽  
E. Cunha ◽  
...  
Keyword(s):  
Inelastic Neutron Scattering ◽  
Inelastic Neutron ◽  
Skeletal Remains ◽  
Anaerobic Conditions ◽  
Human Skeletal Remains ◽  
Human Bones ◽  
Reducing Conditions ◽  
Wide Range ◽  
Burned Bones ◽  
Vibrational Bands

AbstractComplementary optical and neutron-based vibrational spectroscopy techniques (Infrared, Raman and inelastic neutron scattering) were applied to the study of human bones (femur and humerus) burned simultaneously under either aerobic or anaerobic conditions, in a wide range of temperatures (400 to 1000 °C). This is the first INS study of human skeletal remains heated in an oxygen-deprived atmosphere. Clear differences were observed between both types of samples, namely the absence of hydroxyapatite’s OH vibrational bands in bone burned anaerobically (in unsealed containers), coupled to the presence of cyanamide (NCNH2) and portlandite (Ca(OH)2) in these reductive conditions. These results are expected to allow a better understanding of the heat effect on bone´s constituents in distinct environmental settings, thus contributing for an accurate characterisation of both forensic and archaeological human skeletal remains found in distinct scenarios regarding oxygen availability.

scholarly journals Antimicrobial Nodule-Specific Cysteine-Rich Peptides Induce Membrane Depolarization-Associated Changes in the Transcriptome of Sinorhizobium meliloti

2013 ◽  
Vol 79 (21) ◽  
pp. 6737-6746 ◽  
Author(s):  
Hilda Tiricz ◽  
Attila Szűcs ◽  
Attila Farkas ◽  
Bernadett Pap ◽  
Rui M. Lima ◽  
...  
Keyword(s):  
Stress Responses ◽  
Sinorhizobium Meliloti ◽  
Antimicrobial Agents ◽  
Cellular Functions ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Peptide Family ◽  
Wide Range ◽  
Natural Target

ABSTRACTLeguminous plants establish symbiosis with nitrogen-fixing alpha- and betaproteobacteria, collectively called rhizobia, which provide combined nitrogen to support plant growth. Members of the inverted repeat-lacking clade of legumes impose terminal differentiation on their endosymbiotic bacterium partners with the help of the nodule-specific cysteine-rich (NCR) peptide family composed of close to 600 members. Among the few tested NCR peptides, cationic ones had antirhizobial activity measured by reduction or elimination of the CFU and uptake of the membrane-impermeable dye propidium iodide. Here, the antimicrobial spectrum of two of these peptides, NCR247 and NCR335, was investigated, and their effect on the transcriptome of the natural targetSinorhizobium melilotiwas characterized. Both peptides were able to kill quickly a wide range of Gram-negative and Gram-positive bacteria; however, their spectra were only partially overlapping, and differences were found also in their efficacy on given strains, indicating that the actions of NCR247 and NCR335 might be similar though not identical. Treatment ofS. meliloticultures with either peptide resulted in a quick downregulation of genes involved in basic cellular functions, such as transcription-translation and energy production, as well as upregulation of genes involved in stress and oxidative stress responses and membrane transport. Similar changes provoked mainly in Gram-positive bacteria by antimicrobial agents were coupled with the destruction of membrane potential, indicating that it might also be a common step in the bactericidal actions of NCR247 and NCR335.

scholarly journals Using chemical biology to assess and modulate mitochondria: progress and challenges

2017 ◽  
Vol 7 (2) ◽  
pp. 20160151 ◽  
Author(s):  
Angela Logan ◽  
Michael P. Murphy
Keyword(s):  
Mitochondrial Function ◽  
Chemical Biology ◽  
Biomedical Sciences ◽  
Interdisciplinary Approaches ◽  
Wide Range ◽  
Challenges And Opportunities ◽  
Future Challenges ◽  
The Many ◽  
Opening Up

Our understanding of the role of mitochondria in biomedical sciences has expanded considerably over the past decade. In addition to their well-known metabolic roles, mitochondrial are also central to signalling for various processes through the generation of signals such as ROS and metabolites that affect cellular homeostasis, as well as other processes such as cell death and inflammation. Thus, mitochondrial function and dysfunction are central to the health and fate of the cell. Consequently, there is considerable interest in better understanding and assessing the many roles of mitochondria. Furthermore, there is also a growing realization that mitochondrial are a promising drug target in a wide range of pathologies. The application of interdisciplinary approaches at the interface between chemistry and biology are opening up new opportunities to understand mitochondrial function and in assessing the role of the organelle in biology. This work and the experience thus gained are leading to the development of new classes of therapies. Here, we overview the progress that has been made to date on exploring the chemical biology of the organelle and then focus on future challenges and opportunities that face this rapidly developing field.

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