Autophagy promotes cell survival by maintaining NAD(H) levels

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.

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Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

10.1101/2020.01.31.928424 ◽

2020 ◽

Cited By ~ 2

Author(s):

Lucia Sedlackova ◽

Elsje G. Otten ◽

Filippo Scialo ◽

David Shapira ◽

Tetsushi Kataura ◽

...

Keyword(s):

Cell Death ◽

Animal Models ◽

Critical Role ◽

Intervention Strategy ◽

Human Diseases ◽

Lysosomal Storage ◽

Cellular Functions ◽

Tissue Degeneration ◽

Effective Intervention Strategy ◽

The Many

Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components1. As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation2. Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders3–7. However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD+/NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21186881 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6881 ◽

Cited By ~ 2

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.

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The expression of the gene asebia in the laboratory mouse: I. Epidermis and dermis

Genetics Research ◽

10.1017/s0016672300017791 ◽

1978 ◽

Vol 31 (1) ◽

pp. 53-65 ◽

Cited By ~ 28

Author(s):

Wendy J. Josefowicz ◽

Margaret H. Hardy

Keyword(s):

Laboratory Mouse ◽

Lysosomal Storage Diseases ◽

Dermal Fibroblasts ◽

Lysosomal Storage ◽

Sebaceous Glands ◽

Intercellular Spaces ◽

Dermal Layer ◽

Surrounding Matrix ◽

Cellular Debris ◽

The Many

SUMMARYMice homozygous for the asebia mutation (ab/ab), which have defective sebaceous glands, display abnormalities in several other aspects of the integument. Histological sections showed that hyperplasia of the cellular layers and the stratum corneum of the epidermis is apparent at birth and increases markedly with age. Enlarged intercellular spaces are also noted in the epidermis. The thicker dermal layer of the asebic mice is characterized by increased vascularity, increased cellularity and the abnormal morphology of a large proportion of the ‘fibroblast’ population. Electron microscopy demonstrated the many abnormalities in the dermal fibroblasts as well as large amounts of cellular debris in the surrounding matrix. Collagen and elastin show alterations at the light microscopic and ultrastructural levels. Many features of the asebic dermis resemble those found with mild inflammation and with the lysosomal storage diseases. Changes in the dermis of asebic foetuses were noted prior to epidermal alterations and may mediate the latter.

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Gaucher disease and other storage disorders

Hematology ◽

10.1182/asheducation.v2012.1.13.3797921 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 13-18 ◽

Cited By ~ 50

Author(s):

Gregory A. Grabowski

Keyword(s):

Gaucher Disease ◽

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Intracellular Enzyme ◽

Nonalcoholic Fatty Liver ◽

Common Diseases ◽

Age Related ◽

Niemann Pick ◽

Apoptotic Pathways ◽

The Impact

Abstract In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a “primary epithelioma of the spleen.” The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

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Lysosphingolipids and mitochondrial function. II. Deleterious effects of sphingosylphosphorylcholine

Biochemistry and Cell Biology ◽

10.1139/o88-153 ◽

1988 ◽

Vol 66 (12) ◽

pp. 1322-1332 ◽

Cited By ~ 16

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.

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A corynecaterium glutamicum expression system for glycoside hydrolase analysis

10.32920/ryerson.14646525.v1 ◽

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.

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A corynecaterium glutamicum expression system for glycoside hydrolase analysis

10.32920/ryerson.14646525 ◽

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

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Electron Microscopy in the diagnosis of lysosomal storage diseases

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100156316 ◽

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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