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 Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases

2019 ◽  
Vol 20 (2) ◽  
pp. 327 ◽  
Author(s):  
Paola Faverio ◽  
Anna Stainer ◽  
Federica De Giacomi ◽  
Serena Gasperini ◽  
Serena Motta ◽  
...  
Keyword(s):  
Sleep Apnea Syndrome ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Airway Disease ◽  
Pulmonary Involvement ◽  
Molecular Pathways ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Obstructive Sleep ◽  
Wide Range

Lysosomal storage diseases (LSD) include a wide range of different disorders with variable degrees of respiratory system involvement. The purpose of this narrative review is to treat the different types of respiratory manifestations in LSD, with particular attention being paid to the main molecular pathways known so far to be involved in the pathogenesis of the disease. A literature search was conducted using the Medline/PubMed and EMBASE databases to identify studies, from 1968 through to November 2018, that investigated the respiratory manifestations and molecular pathways affected in LSD. Pulmonary involvement includes interstitial lung disease in Gaucher’s disease and Niemann-Pick disease, obstructive airway disease in Fabry disease and ventilatory disorders with chronic respiratory failure in Pompe disease due to diaphragmatic and abdominal wall muscle weakness. In mucopolysaccharidosis and mucolipidoses, respiratory symptoms usually manifest early in life and are secondary to anatomical malformations, particularly of the trachea and chest wall, and to accumulation of glycosaminoglycans in the upper and lower airways, causing, for example, obstructive sleep apnea syndrome. Although the molecular pathways involved vary, ranging from lipid to glycogen and glycosaminoglycans accumulation, some clinical manifestations and therapeutic approaches are common among diseases, suggesting that lysosomal storage and subsequent cellular toxicity are the common endpoints.

scholarly journals Lysosome function in glomerular health and disease

2021 ◽  
Author(s):  
Catherine Meyer-Schwesinger
Keyword(s):  
Current Knowledge ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Membrane Repair ◽  
Glomerular Cell ◽  
Wide Range ◽  
Center Position ◽  
Health And Disease

AbstractThe lysosome represents an important regulatory platform within numerous vesicle trafficking pathways including the endocytic, phagocytic, and autophagic pathways. Its ability to fuse with endosomes, phagosomes, and autophagosomes enables the lysosome to break down a wide range of both endogenous and exogenous cargo, including macromolecules, certain pathogens, and old or damaged organelles. Due to its center position in an intricate network of trafficking events, the lysosome has emerged as a central signaling node for sensing and orchestrating the cells metabolism and immune response, for inter-organelle and inter-cellular signaling and in membrane repair. This review highlights the current knowledge of general lysosome function and discusses these findings in their implication for renal glomerular cell types in health and disease including the involvement of glomerular cells in lysosomal storage diseases and the role of lysosomes in nongenetic glomerular injuries.

scholarly journals Lysosomes and Their Role in Mucopolysaccharide Disorders: New Insights

2018 ◽  
Vol 08 (01) ◽  
pp. e151-e155
Author(s):  
Susanne Kircher ◽  
Thomas Taylor
Keyword(s):  
Connective Tissue ◽  
Lysosomal Storage Diseases ◽  
Degradation Process ◽  
Chronic Arthritis ◽  
Lysosomal Storage ◽  
Cell Organelles ◽  
Skeletal Changes ◽  
Wide Range ◽  
Unexpected Findings ◽  
Small Chemical

AbstractMucopolysaccharidoses (MPS) belong to the group of lysosomal storage diseases and are characterized by the deficiency of lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). They are caused by inherited enzyme deficiencies that result from mutated genes producing defective enzymes. In MPS, the step-wise degradation process of GAG chains is impaired, and thus pieces of undegraded chains remain in the lysosomes impeding other processes in these cell organelles. Several enzymes—currently 12 are known—are necessary to degrade GAGs to sugars and small chemical substances, such as sulfate- or amino groups, to prepare them for excretion via exocytosis or to reintegrate them into new molecules by recycling. GAGs are major components of the connective tissue but play a role in shaping the vicinity of each cell surface as well; hence, any disturbance in their metabolism causes problems not limited to connective tissue but other tissues and organs. Therefore, MPS are multisystemic diseases involving many organs and restrict a wide range of organ functions. Organomegaly, typical skeletal changes known as “dysostosis multiplex,” excessive storage in the nervous system with neurologic symptoms and impaired cognitive function have been known as the typical symptoms of the first classical MPS types for some time now. Because of new therapies and improved care, the life expectancy of MPS patients has increased significantly. Results of investigations that have only become available recently and new methods allowing for fine-meshed observation have revealed unexpected findings. These outcomes are not limited to excessive storage: patients show unpredictable reactions of the immune system, chronic inflammation, changes in metabolic pathways not directly related to the connective tissue, such as chronic arthritis, osteopenia, Parkinson-like symptoms, signs of dementia, and many more, which suggest that lysosomes have many more roles than just degradation of no longer needed macromolecules.

scholarly journals Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

2020 ◽  
Vol 21 (18) ◽  
pp. 6881 ◽  
Author(s):  
Alex E. Ryckman ◽  
Inka Brockhausen ◽  
Jagdeep S. Walia
Keyword(s):  
Membrane Lipids ◽  
Lysosomal Storage Diseases ◽  
Sandhoff Disease ◽  
Eukaryotic Cells ◽  
Head Group ◽  
Cell Recognition ◽  
Lysosomal Storage ◽  
Cellular Functions ◽  
Key Features ◽  
Storage Disorders

Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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.

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.

scholarly journals A corynecaterium glutamicum expression system for glycoside hydrolase analysis

2021 ◽  
Author(s):  
Hirak Saxena
Keyword(s):  
Expression System ◽  
Lysosomal Storage Diseases ◽  
Industrial Applications ◽  
Glycoside Hydrolases ◽  
Cellulosic Biomass ◽  
Lysosomal Storage ◽  
Cellular Functions ◽  
Domains Of Life ◽  
Hydrolysis Of ◽  
Structure And Activity

The biological hydrolysis of glycosidic linkages in complex sugars is facilitated by glycoside hydrolases. These enzymes are ubiquitous across all domains of life, playing significant roles in important biological processes like the degradation of cellulosic biomass, viral pathogenesis, antibacterial defense, and normal cellular functions. The potential industrial applications of highly efficient glycoside hydrolases, as well as the fact that a number of lysosomal storage diseases have been attributed to deficiencies in these enzymes 43, 22, merits further study into their structure and activity. For this reason, a handful of novel glycoside hydrolases from Cellulomonas fimi, a Gram-positive Actinobacteria known for its ability to degrade cellulose 39, will be cloned, expressed and biochemically analyzed.

Autophagy promotes cell survival by maintaining NAD(H) levels

2021 ◽  
Author(s):  
Lucia Sedlackova ◽  
Tetsushi Kataura ◽  
Elena Seranova ◽  
Congxin Sun ◽  
Elsje Otten ◽  
...  
Keyword(s):  
Cell Survival ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Cellular Functions ◽  
Cellular Survival ◽  
Tissue Degeneration ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Membrane Depolarisation ◽  
The Many

Abstract Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites to aid metabolic homeostasis2. Loss of autophagy in animal models or malfunction of this process in a number of age-related human pathologies, including neurodegenerative and lysosomal storage diseases, contributes to tissue degeneration3-9. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD+/NADH) levels, which are critical for cellular survival. In respiring cells, loss of autophagy caused hyperactivation of PARP and Sirtuin families of NADases. Uncontrolled depletion of NAD(H) pool by these enzymes resulted in mitochondrial membrane depolarisation and cell death. Supplementation with NAD(H) precursors improved cell viability in autophagy-deficient models including human pluripotent stem cell-derived neurons with autophagy deficiency or patient-derived neurons with autophagy dysfunction. Our study provides a mechanistic link between autophagy and NAD(H) metabolism, and suggests that boosting NAD(H) levels may have therapeutic benefits in human diseases associated with autophagy dysfunction.

scholarly journals A corynecaterium glutamicum expression system for glycoside hydrolase analysis

2021 ◽  
Author(s):  
Hirak Saxena
Keyword(s):  
Expression System ◽  
Lysosomal Storage Diseases ◽  
Industrial Applications ◽  
Glycoside Hydrolases ◽  
Cellulosic Biomass ◽  
Lysosomal Storage ◽  
Cellular Functions ◽  
Domains Of Life ◽  
Hydrolysis Of ◽  
Structure And Activity

The biological hydrolysis of glycosidic linkages in complex sugars is facilitated by glycoside hydrolases. These enzymes are ubiquitous across all domains of life, playing significant roles in important biological processes like the degradation of cellulosic biomass, viral pathogenesis, antibacterial defense, and normal cellular functions. The potential industrial applications of highly efficient glycoside hydrolases, as well as the fact that a number of lysosomal storage diseases have been attributed to deficiencies in these enzymes 43, 22, merits further study into their structure and activity. For this reason, a handful of novel glycoside hydrolases from Cellulomonas fimi, a Gram-positive Actinobacteria known for its ability to degrade cellulose 39, will be cloned, expressed and biochemically analyzed.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

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