ArticleThe Journal of biological chemistry2014
Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Mitochondrial Transfer in the Neurovascular Unit, Not Only for Energy Rescue: A Systematic Review.Aging and disease · 2024Pooled it
- Metabolomics of cerebrospinal fluid following traumatic brain injury: Exploration of biomarkers for secondary injuries and severity.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Mechanism of fumonisin B1 on growth performance and intestinal structural integrity of juvenile grass carp (Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2025Article
- Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases.Lipids in health and disease · 2024Article
- Integrative Analysis of Cytokine and Lipidomics Datasets Following Mild Traumatic Brain Injury in Rats.Metabolites · 2024Article
- Hydrogel in the Treatment of Traumatic Brain Injury.Biomaterials research · 2024Review
- The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases.Current topics in medicinal chemistry · 2024Review
- Article
- Compartmentalization of Sphingolipid metabolism: Implications for signaling and therapy.Pharmacology & therapeutics · 2022Review
- Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury.Journal of lipid research · 2022Article
- Inhibition of extracellular vesicle pathway using neutral sphingomyelinase inhibitors as a neuroprotective treatment for brain injury.Neural regeneration research · 2021Review
- Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.Molecular neurobiology · 2021Article
- Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities.International journal of molecular sciences · 2021Review
- Sphingosine kinase 1 downregulation is required for adaptation to serine deprivation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes.Frontiers in endocrinology · 2021Review
- COX5A Plays a Vital Role in Memory Impairment Associated With Brain AgingFrontiers in aging neuroscience · 2020Article
- Review
- Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury.The Journal of pharmacology and experimental therapeutics · 2019Article
- Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury.Journal of lipid research · 2019Article
- Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases.Frontiers in pharmacology · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
In addition to immediate brain damage, traumatic brain injury (TBI) initiates a cascade of pathophysiological events producing secondary injury. The biochemical and cellular mechanisms that comprise secondary injury are not entirely understood. Herein, we report a substantial deregulation of cerebral sphingolipid metabolism in a mouse model of TBI. Sphingolipid profile analysis demonstrated increases in sphingomyelin species and sphingosine concurrently with up-regulation of intermediates of de novo sphingolipid biosynthesis in the brain. Investigation of intracellular sites of sphingosine accumulation revealed an elevation of sphingosine in mitochondria due to the activation of neutral ceramidase (NCDase) and the reduced activity of sphingosine kinase 2 (SphK2). The lack of change in gene expression suggested that post-translational mechanisms are responsible for the shift in the activities of both enzymes. Immunoprecipitation studies revealed that SphK2 is complexed with NCDase and cytochrome oxidase (COX) subunit 1 in mitochondria and that brain injury hindered SphK2 association with the complex. Functional studies showed that sphingosine accumulation resulted in a decreased activity of COX, a rate-limiting enzyme of the mitochondrial electron transport chain. Knocking down NCDase reduced sphingosine accumulation in mitochondria and preserved COX activity after the brain injury. Also, NCDase knockdown improved brain function recovery and lessened brain contusion volume after trauma. These studies highlight a novel mechanism of secondary TBI involving a disturbance of sphingolipid-metabolizing enzymes in mitochondria and suggest a critical role for mitochondrial sphingosine in promoting brain injury after trauma.
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Registered trials
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